Methods and systems for the treatment of polycystic ovary syndrome

ABSTRACT

Described here are methods and systems for the manipulation of ovarian tissues. The methods and systems may be used in the treatment of polycystic ovary syndrome (PCOS). The systems and methods may be useful in the treatment of infertility associated with PCOS.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/892,943 filed on Oct. 18, 2013 and U.S. Provisional ApplicationSerial No. 61/969,042 filed on Mar. 21, 2014, the disclosures of whichare herein incorporated by reference in their entirety.

FIELD

Described here are methods and systems for the manipulation of ovariantissues. The methods and systems may be used in the treatment ofpolycystic ovary syndrome (PCOS). The systems and methods may be usefulin the treatment of infertility associated with PCOS.

BACKGROUND

Polycystic Ovary Syndrome (PCOS) was initially characterized in the1930s by Stein & Leventhal. Features of the syndrome may include:oligo/amenorrhea, oligo/anovulation, hirsutism, acne, obesity, andcharacteristic polycystic appearance of the ovaries, PCOS generally hassignificant effects on reproductive health (e.g., igo/amenorrhea andoligo/anovulation, bleeding, endometrial hyperplasia, infertility, andincreased risk of endometrial cancers) as well as non-reproductivehealth (e.g., hyperandrogenism, carcinoma, insulin resistance,hypercholesterolemia, hypertension, obesity, sleep apnea, andcardiovascular disease). PCOS has historically been considered in thecontext of hormonal dysregulation characterized by alterations ingonadotropin secretion, increased androgen production, increased insulinresistance, increased cortisol production, and obesity. It has also beenshown that PCOS is often accompanied by increased activity of thesympathetic nervous system.

Treatment of PCOS can be costly to the health care system. Keynon-infertility treatments include: oral contraceptives (for hormonalnormalization), endometrial ablation (for anovulatory bleeding), insulinsensitizing agents, anti-hypertensive agents, statins, and treatmentsfor severe acne and hirsutism.

Many women with PCOS may also require infertility treatment during theirlifetime. Treatment for PCOS infertility typically follows a step-wiseapproach. For example, clomiphene citrate is generally the first-linetreatment with second-line treatment being either gonadotropinadministration or ovarian drilling (also sometimes referred to asovarian diathermy). If these treatments are unsuccessful, in vitrofertilization (WE) is attempted. However, multiple pregnancies and livebirths (e.g., twins) are common with clomiphene citrate, gonadotropin,and IVF treatments. In infertility treatment, multiple pregnancies andlive births is often considered an undesirable result due to theassociated perinatal and neonatal morbidity and the associated elevatedcosts. Furthermore, ovarian hyperstimulation syndrome (GIBS) may be morecommon in women with PCOS undergoing gonadotropin or WE treatment. WhileOHSS is often mild and easily treated, more severe cases may requireaggressive treatment.

Alternatively, and as mentioned above, ovarian drilling may be an optionin treating PCOS, PCOS-associated symptoms/disorders, and PCOS relatedinfertility. Prior to the development of ovarian drilling, many othertypes of surgery were performed on the ovaries for the treatment ofinfertility, Ovarian wedge resection, a well-established procedure firstdescribed in the late 1940s, involves surgically removing wedge-shapedpieces of ovarian tissue from polycystic ovaries. Despite theeffectiveness of the procedure, ovarian wedge resection has generallybeen abandoned in favor of new techniques because of the frequentoccurrence of adhesions with the wedge resection technique. Otherovarian surgeries for infertility in PCOS that have been performed areovarian electrocautery, ovarian laser vaporization, multiple ovarianbiopsies, and others.

Ovarian drilling/diathermy (OD) was developed in the 1970s and 1980s byGjönnaess. Recently, OD has been the most frequently described ovariansurgery for infertility in women with PCOS. In this laparoscopicprocedure, radiofrequency energy, or other techniques, is used to boremultiple holes in the ovary. The physiologic mechanism is not welldocumented, but there are common findings following the surgeryincluding acute changes in ovarian and pituitary hormones followed by aprolonged reduction of circulating androgens. In randomized trials,rates of pregnancy and live birth have been shown to be similar to thoseassociated with gonadotropin treatment, but with significantly reducedrates of multiple pregnancies and live births.

Despite this evidence, ovarian drilling is not used as frequently inclinical practice as other treatments for PCOS infertility. This may bedue to: (1) the lack of standardized, consistent methods of targetingand performing surgeries on the ovary; (2) the invasive nature ofcurrent OD technologies: (3) the theoretical risk of adhesions fromintervention on the ovaries; (4) the surgical route of access is not agood fit for the clinical practice patterns of fertility physicians; and(5) the uncertainty of the mechanism of action. Accordingly, it would beuseful to have systems and methods that overcome the limitations ofcurrent surgical procedures. Such systems may be designed toconsistently target ovarian tissues, reduce the level of invasiveness ofthe procedure, reduce the risk of adhesions, and potentially targetspecific tissue types to act more specifically tissues responsible forthe disease. Moreover, given that the ovaries or elements therein mayplay an important role in governing other female health issues such astiming of menopause, hot-flushes, fibroids, hormonal dysregulation,endometriosis, adnexal pain, risk of endometrial cancer, disturbances inglucose metabolism, or cardiovascular health, it would be beneficial tohave improved methods and systems for treating these conditions as wellas targeting of structures within or nearby the ovaries that may enabletreatment of these conditions.

SUMMARY

Described here are methods and systems for manipulating ovarian tissueswithin a patient. Exemplary ovarian tissues include without limitation,the ovaries (e.g., medulla/stroma and/or cortex), ovarianfollicles/cysts, nerves associated with the ovaries, suspensoryligaments, ovarian ligaments, broad ligaments, the mesovarium, or acombination thereof. In this application, the terms medulla and stromaare used interchangeably. Stromal tissue generally comprises the middleor medullary region of the ovary. The cortex (or outer region) of theovary is generally where follicles of different degrees of maturity tendto reside. These follicles are sometimes called “cysts” in the settingof PCOS, and in this application, follicle and cyst are usedinterchangeably. The methods and systems may be used to treat one ormore symptoms of, or disorders associated with, polycystic ovarysyndrome, including infertility.

In general, the methods and systems are configured to access ovariantissue or a target region proximate the ovarian tissue transvaginally,laparoscopically, percutaneously, via a natural orifice route throughthe vagina-uterus-fallopian tubes, through an open surgical approach orvia an entirely non-invasive approach. The methods and systems may treatovarian tissues by mechanical manipulation and/or removal, by deliveryof chemical, biologic, or pharmaceutical agents, by delivery of energy,or by applying cooling/cold to the tissues. Exemplary treatmentmodalities may include without limitation, delivery of one or more ofthe following: a radiofrequency energy element; a direct heatingelement; a cryoablation element; a cooling element; a mechanicaldisruption and/or removal element; laser; a microwave antenna; anunfocused ultrasound element; a partially-focused ultrasound element; afocused (HIFU) ultrasound element; and/or an element for deliveringheated water/saline, steam, a chemical ablation agent, a biologic orpharmaceutical agent, implantable pulse generator, a passive or active(e.g., electronic drug delivery unit) drug-eluting implant, aradioisotope seed, or a mechanical implant, which may be either passiveor active via application of remote energy (e.g., ultrasound to inducevibration).

The systems described here generally comprise an ovarian tissueapparatus capable of being advanced proximate to or within an ovary, andin the case of PCOS, an ovarian follicle/cyst or other target tissue(e.g., stroma). The ovarian tissue apparatus may also include anengagement device, e.g., a docking device, configured to engage ovariantissue. The engagement device may be configured to engage the outsidesurface of the ovary (e.g., the capsule), the outer _regions of tissuewithin the ovary (e.g., the cortex), or the tissue inside the ovary(e.g., medulla, one or more cysts). One or more therapeutic elements canbe deployed via the devices to apply one treatment or multipletreatments to the ovarian cyst and/or ovarian tissue. The therapeuticelements may deliver energy, e.g., radiofrequency energy, to effecttreatment. The devices and therapeutic elements may be advanced,deployed, or otherwise positioned under image guidance, (e.g.,transvaginal ultrasound, transabdominal ultrasound, endoscopicvisualization, direct visualization, computed tomography (CT), ormagnetic resonance imaging (MRI), optical coherence tomography (OCT), anultrasound element on the device, or virtual histology). Pre-treatmentplanning may also be completed prior to performance of the procedure onthe target tissue. For example, one or more of the following may beobtained; the size, volume, and/or location of the ovary; the size,volume and/or location of one or more ovarian cysts; and the size,volume, and/or location of the medulla, hormone levels, etc.

According to some embodiments described herein, which may partially oras a whole combine with other embodiments, systems for performing anovarian procedure may include an ovarian tissue apparatus, the ovariantissue apparatus comprising a docking device and a therapeutic element,the docking device comprising an elongate body and having a proximalend, a distal end, and defining a lumen therethrough, and thetherapeutic element being slidable within and deployable from the lumenof the docking device; a transvaginal probe comprising a handle and anultrasound transducer; a mechanical lock or a visual identifier on apart of the system; and a generator configured to supply energy to thetherapeutic element, where the mechanical lock or visual identifier isconfigured to maintain planar orientation of the therapeutic elementrelative to the ultrasound transducer and during a procedure on anovary. In some instances a non-linear (e.g., curved) therapeutic elementmay be employed, which allows the therapeutic element to be fullyvisualized under 2-dimensional ultrasound during therapy delivery,thereby ensuring that non-target tissues are not treated. The curvedstructure may further aid in anchoring the device in the target tissue,limiting the risk of the device moving during treatment due to patientmovement or user error. The curved structure may also be configured tomatch the contour of the ovary, allowing for improved positioning withina variety of sized or shaped ovaries. Additionally or alternatively, thecurved structure may allow for longer or additional electrodes to bedelivered and used simultaneously, allowing for larger ablation volumesper energy application. This feature may limit pain experienced by thepatient and reduce procedure time. Anchoring either the docking deviceand/or the therapeutic element in the target tissue may help the user tomove the ovary relative to surrounding non-ovary tissues to improveand/or confirm visualization. Moving the ovary may also allow the userto more easily reposition the device for subsequent treatments.Additionally or alternatively, the docking device may be configured toaid in anchoring the device in the target tissue.

According to embodiments described herein, which may partially or as awhole combine with other embodiments, systems for performing an ovarianprocedure may include a docking device, the docking device comprising anelongate body and having a proximal end, a distal end, and defining alumen therethrough; a radiofrequency energy element slidable within anddeployable from the lumen of the docking device; a transvaginal probecomprising a handle and an ultrasound transducer; a mechanical lock forreleasably coupling the docking device to the probe handle to maintainplanar orientation of the radiofrequency energy element relative to theultrasound transducer during the ovarian procedure; and a generatorconfigured to supply radiofrequency energy to the radiofrequency energyelement. In some instances a non-linear (e.g., curved) therapeuticelement may be employed, which allows the therapeutic element to befully visualized under 2-dimensional ultrasound during therapy delivery,thereby ensuring that non-target tissues are not treated. As previouslystated, the curved structure may further aid in anchoring the device inthe target tissue, limiting the risk of the device moving duringtreatment due to patient movement or user error. The curved structuremay also be configured to match the contour of the ovary, allowing forimproved positioning within a variety of sized or shaped ovaries.Additionally or alternatively, the curved structure may allow for longeror additional electrodes to be delivered and used simultaneously,allowing for larger ablation volumes per energy application. Thisfeature may limit pain experienced by the patient and reduce proceduretime.

Instead of being releasably coupled to the docking device, in someembodiments the mechanical lock is fixedly attached to the dockingdevice. This system embodiment may have a variety of effects therapy.This system embodiment, e.g., may allow for a minimally-invasive,transvaginal approach, wherein the ovary would be accessed using thedocking device. By having the docking device resemble a sharp needle,the docking device may be used to puncture through the vaginal wall andinto the ovary under transvaginal image guidance. In some cases, thismay allow for a single entry point or fewer entry points into the ovary,reducing the risk of adhesions as compared to surgical and laparoscopicapproaches with tissue dissection and entry points for each ablation inthe ovary. Once in position, the radiofrequency energy element may bedeployed into the tissue. In the case where a mechanical lock is used tomaintain planar orientation of the radiofrequency element, theradiofrequency element may be non-linear (e.g., curved in a singleplane). Here the releasably securable mechanical lock allows thetherapeutic element to be flipped 180 degrees so in the case of anasymmetrically shaped therapeutic element, additional regions of theovary could he accessed and treated without moving the deliverycatheter. The non-releasable version of the lock simplifies the userexperience when a therapeutic element does not need to be flipped 180degrees. Since transvaginal ultrasound imaging provides a 2-dimensionalimage, it is important to maintain the orientation of the radiofrequencyelement to ensure that the user can see the entire structure. Thisallows the user to visually observe deployment and confirm positionwithin the ovary or target tissue, adding to the safety and/oreffectiveness of the procedure. The advantages of a transvaginalapproach over surgical or laparoscopic approaches generally include oneor more of the following: (a) conscious sedation vs. general anesthesiawhich reduces cost and patient risk, (b) no external scars, (c) lesstissue manipulation resulting in lower risk of adhesions, (d) feweraccess points into the ovary resulting in lower risk of adhesions, (e)faster recovery time, and (f) it is a familiar access route for OB/GYNand fertility physicians, and fits within existing care pathways.

According to some embodiments described herein, which may partially oras a whole combine with other embodiments, systems described herein maycomprise additionally or alternatively an ultrasound imaging and/ortherapeutic element configured to be placed in contact with the abdomenof a patient; an element(s) for operatively connecting the ultrasoundimaging and/or therapeutic element to a console, comprised of a userinterface, an element(s) for delivering ultrasound for imaging, anelement(s) for targeting desired tissue, an element(s) for deliveringenergy (e.g., partially-focused ultrasound, HIFU), and an element(s) fora feedback control system.

Methods for manipulating ovarian tissue of a patient may includedelivering pain management medications systemically and/or locally(e.g., the vaginal wall, the ovary, the mesovarium), accessing a targetregion proximate an ovarian tissue within the patient; advancing anovarian tissue apparatus to the target region, the ovarian tissueapparatus comprising a docking device and one or more therapeuticelements, the docking device comprising a proximal end, a distal end,and a distal tip; moving the docking device proximate to or within theovarian tissue; deploying the one or more therapeutic elements on orwithin the ovarian tissue; assessing intra-procedural success; andminimizing the occurrence of adhesions as seen with surgical approachesused in the past. The docking device may or may not require physicalcontact with ovarian tissues.

In some instances, it may be useful to employ methods that minimize theoccurrence of adhesion such as performing the procedure via a singleentry point or fewer entry points in the ovary (the severity ofadhesions may correlate with the number and size of damage to the ovarysurface); avoiding injury to the cortex or regions of the cortex closestto the surface (e.g., several millimeters) of the ovary; and leavingbehind material anti-adhesive barriers to improve healing at the ovarysurface and further reduce adhesion formation. It may also be beneficialto include features for visualizing various portions of the system usingimaging as a guide. Depending upon the approach taken (e.g.,transvaginal, percutaneous, laparoscopic), the apparatus may includevarious mechanisms for improving visualization of the portions of thesystem, e.g., the therapeutic elements.

Methods described herein for delivering energy to an ovary and fortreating polycystic ovary syndrome may include advancing a probecomprising a handle, an ultrasound transducer, and a needle guide intothe vaginal canal; advancing an ovarian tissue apparatus into the needleguide, the ovarian tissue apparatus comprising a docking device and atherapeutic element; advancing the docking device through a vaginalwall; penetrating an ovary at a single entry point with the dockingdevice or the therapeutic element; advancing the therapeutic elementfrom the docking device into the ovary; and delivering energy to affecta volume of tissue within the ovary using the therapeutic element totreat a symptom of polycystic ovary syndrome; retracting the therapeuticelement into the docking device; and removing the ovarian tissueapparatus.

Alternative methods for treating polycystic ovary syndrome as describedherein may include advancing an ovarian ablation system into the vaginalcanal, the ovarian ablation system comprising a docking device, aradiofrequency energy element, and a transvaginal probe comprising ahandle and an ultrasound transducer; advancing the docking devicethrough a vaginal wall under image guidance using the ultrasoundtransducer: entering an ovary through a single entry point using thedocking device or the radiofrequency energy element; advancing theradiofrequency energy element within the ovary; and deliveringradiofrequency energy to ablate a volume of tissue within the ovaryusing the radiofrequency energy element to treat a symptom of polycysticovary syndrome.

Methods that may be useful in treating polycystic ovary syndrome arealso described herein. Such methods generally include advancing anovarian tissue apparatus proximate a polycystic ovary within a patient,the ovarian tissue apparatus comprising a docking device and one or moretherapeutic elements, the docking device comprising a proximal end, adistal end, and a distal tip; deploying the one or more therapeuticelements from the docking device proximate to or within a target tissue,e.g., an ovarian cyst; and manipulating the polycystic ovary to effect achange in the target tissue, one or more symptoms or physiologicalparameters indicative of polycystic ovary syndrome or its relatedsymptoms, diseases, disorders, or a combination thereof.

Methods that may be useful in controlling pain associated withnon-surgical procedures are also described herein. Such methodsgenerally include delivering systemic pharmacologic sedation (e.g.,monitored anesthesia care (MAC) or conscious sedation); delivering localanesthesia to the vaginal wall to reduce discomfort in a transvaginalprocedure: delivering local anesthesia to the ovary, target tissue,mesovarium, or nerve tissue proximate to the ovary to minimizediscomfort associated with application of the therapy; and delivering anepidural to minimize discomfort and patient movement during theprocedure.

Methods that may be useful in determining the intra-procedural orpost-procedural effect of the procedure are also described herein. Suchmethods generally include comparing pre-treatment planning parameters(e.g., the size, volume, and/or location of the ovary; the size, volumeand/or location of one or more ovarian cysts; the size, volume, and/orlocation of the medulla; hormone levels) withintra-procedurally-measured parameters or post-procedurally-measuredparameters. Examples include: a visible reduction in ovary size orvolume, a reduction in the number of cysts, or a reduction in hormonelevels, such as anti-müllerian hormone.

According to some embodiments described herein, and which may partiallyor as a whole combine with other embodiments, systems for manipulatingovarian tissues generally include an ovarian tissue apparatus configuredfor advancement through the vaginal wall and proximate an ovariantissue; and an energy generator electrically coupled to the ovariantissue apparatus, where the ovarian tissue apparatus comprises a dockingdevice and one or more therapeutic elements, the docking devicecomprising an elongate body having a proximal end, a distal end, a lumenextending from the proximal end through the distal end, and a distaltip. in some instances a non-linear (e.g., curved) therapeutic elementmay be employed, which allows the therapeutic element to be fullyvisualized under 2-dimensional ultrasound during therapy delivery,thereby ensuring that non-target tissues are not treated. As previouslystated, the curved structure may further aid in anchoring the device inthe target tissue, limiting the risk of the device moving duringtreatment due to patient movement or user error. The curved structuremay also be configured to match the contour of the ovary, allowing forimproved positioning within a variety of sized or shaped ovaries.Additionally or alternatively, the curved structure may allow for longeror additional electrodes to be delivered and used simultaneously,allowing for larger ablation volumes per energy application. Thisfeature may limit pain experienced by the patient and reduce proceduretime. Anchoring either the docking device and/or the therapeutic elementin the target tissue may help the user to move the ovary relative tosurrounding non-ovary tissues to improve and/or confirm visualization.Moving the ovary may also allow the user to more easily reposition thedevice for subsequent treatments. Additionally or alternatively, thedocking device may be configured to aid in anchoring the device in thetarget tissue. In some embodiments, a cooling or cryogenic console maybe operatively coupled to the ovarian tissue apparatus instead of or inaddition to an energy generator. Use of cooling or cryotherapy may limitthe amount of pain the patient experiences and may be used incombination with energy to aid in controlling lesion size (e.g., limitconductive heating). Further, combining cooling or cryotherapy withenergy may allow for thermally cycling target tissue from cold to hot,resulting in additional cellular injury.

According to some embodiments described herein, and which may partiallyor as a whole combine with other embodiments, the system may generallyinclude an ovarian tissue apparatus configured for advancement throughthe vaginal wall and proximate an ovarian tissue; one or more mechanicaldisruption and/or removal elements; and means for removing target tissuefrom the body. Mechanical disruption elements may be manipulatedmanually or automatically (e.g., via a motor and/or drive system).Mechanical manipulations may include rotation, translation and/orvibration. Removal elements may include mechanical instruments forgrasping or capturing tissue or a lumen of the apparatus coupled withaspiration or suction. The removed tissue may be used for diagnosis, orcomponents of removed tissue (e.g. oocytes or cellular factors) may beuseful in further care. In some embodiment, means for removing targettissue from the body may also include allowing the body's naturalhealing process to resorb destroyed tissue and/or produce a stable scar.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts a stylized, anatomic view of the ovaries, adnexa,uterus, and other nearby structures. FIG. 1B depicts a stylized anatomicview of the structural elements within the ovary.

FIGS. 2-5 depict embodiments of devices for creating space in the areaadjacent to the ovary for facilitating a procedure on the ovaries.

FIGS. 6-10 and 11A-11B depict embodiments of guide/docking device andassociated methods for facilitating access to the ovaries.

FIGS. 12A-12F, 13A-13D, 14A-14E, 15A-15B, 16A-16D, 17, 18A-18D, 19,20A-20C, 21A-21B, and 22 depict embodiments of therapeutic elements andmethods for deploying the therapeutic elements for treatment of theovaries.

FIG. 23 depicts an embodiment of a system for energy delivery via atransvaginal, laparoscopic, percutaneous, or surgical procedure.

FIG. 24 depicts an embodiment of a device for providing planarorientation of therapeutic element(s) during transvaginalultrasound-guided procedures.

FIG. 25 shows various views of an embodiment of a magnetic needle guide.

FIG. 26 illustrates an exemplary method for providing planar orientationof a curvilinear therapeutic element.

FIGS. 27A-27F depict another exemplary method and device for providingplanar orientation of therapeutic element(s) during transvaginalultrasound-guided procedures.

FIG. 28 depicts a further embodiment of a device for providing planarorientation of therapeutic element(s) during transvaginalultrasound-guided procedures.

FIG. 29 illustrates an exemplary method of accessing ovarian tissuetransvaginally.

FIG. 30 illustrates an exemplary method of accessing ovarian tissuelaparoscopically.

FIG. 31 depicts another embodiment of a system and method for ablatingovarian tissue.

FIG. 32 depicts an exemplary Power/Temperature Curve.

FIG. 33 depicts another exemplary Power/Temperature Curve.

FIG. 34 depicts an embodiment of a system including a neutral electrodefor measurement of impedance.

FIGS. 35A-35C depict he system of FIG. 34 in varying portions of theovary.

FIGS. 36A-36C illustrates an exemplary method of limiting travel of atherapeutic element into the ovary.

FIG. 37 depicts an embodiment of a non-invasive treatment system.

DETAILED DESCRIPTION

Described here are methods and systems for manipulating ovarian tissueswithin a patient. The methods and systems may be used in the treatmentof polycystic ovary syndrome (PCOS), and may be particularly useful inthe treatment of infertility associated with PCOS. As previously stated,exemplary ovarian tissues include without limitation, the ovaries,ovarian cysts, nerves associated with the ovaries, suspensory ligaments,ovarian ligaments, broad ligaments, the mesovarium, or a combinationthereof.

In general, the methods and systems are configured to access ovariantissue or a target region proximate the ovarian tissue transvaginally,laparoscopically, percutaneously, via a natural orifice route throughthe vagina-uterus-fallopian tubes, through an open surgical approach, orvia an entirely non-invasive approach. It may be beneficial to accessthe ovarian tissue or a target region proximate the ovarian tissuetransvaginally. The advantages of a transvaginal approach over surgicalor laparoscopic approaches may include one or more of the following: (a)conscious sedation vs. general anesthesia which reduces cost and patientrisk, (b) no external scars, (c) less tissue manipulation resulting inlower risk of adhesions, (d) fewer access points into the ovaryresulting in lower risk of adhesions, (e) faster recovery time, and (f)it is a familiar access route for OB/GYN and fertility physicians, andfits within existing care pathways. As used herein, the term“transvaginal” or “transvaginally” refers to access through the vaginaand into the peritoneal space, through the vaginal wall. The methods andsystems may treat ovarian tissues by delivery of one or more of thefollowing: a radiofrequency energy element; a direct heating element; acryoablation element; a cooling element; a mechanical disruptionelement; laser; a microwave antenna; an unfocused ultrasound element; apartially-focused ultrasound element; a focused (HIFU) ultrasoundelement; and/or an element for delivering heated water/saline, steam, achemical ablation agent, a biologic or pharmaceutical agent, implantablepulse generator, a passive or active (e.g., electronic drug deliveryunit) drug-eluting implant, or a mechanical implant, which may be eitherpassive or active via application of remote energy (e.g., ultrasound toinduce vibration).

When the methods and systems employ an image guided energy deliveryelement (therapeutic element), it may be useful to maintain planarorientation of the energy delivery element with an imaging plane ofview, as further described below. In the case of a non-linear (e.g.,curved) therapeutic element, this allows for the therapeutic element tobe fully visualized under 2-dimensional imaging during therapy delivery,thereby ensuring that non-target tissues are not treated. Furthermore,when performing an ovarian procedure with the systems described herein,it may be beneficial to minimize the number of entry points into theovary (the severity of adhesions may correlate with the number and sizeof damage to the ovary surface). After accessing the ovary through thesingle entry point, energy may be delivered from inside the ovary(instead of from outside the ovary) to affect a volume of tissue and/ortreat polycystic ovary syndrome. For example, the number of ablationsneeded to affect the desired volume of tissue may vary, but could rangefrom 1-10 ablations.

To further understand the methods and systems described herein, a briefoverview of female reproductive anatomy is provided. Referring to FIG.1A, the paired ovaries (2) lie within the pelvic cavity, on either sideof the uterus (3), to which they are attached via a fibrous cord calledthe ovarian ligament (4). The ovaries (2) are uncovered in theperitoneal cavity but are tethered laterally to the body wall via thesuspensory ligament (5) of the ovary. The part of the broad ligament (6)of the uterus that suspends the ovary is known as the mesovarium (7).FIG. 1B is an expanded, cross-sectional view of the ovary (2) andsurrounding structures shown in FIG. 1A. Referring to FIG. 1B, thestroma or medulla (8) comprises the middle or medullary region of theovary; the cortex (9) (or outer region) of the ovary tends to be wherefollicles (10) of different degrees of maturity reside; primordialfollicles (12), which are very small and immature follicles, comprise areserve of future follicles for ovulation; a capsule (14) encases theovary (2), which is tethered to the broad ligament (6) by the mesovarium(7); small blood vessels (16) and nerves (18) enter the ovary (2)through the mesovarium (7), the ovarian ligament (4), and the suspensoryligament (5) of the ovary.

A brief overview of several approaches to accessing ovarian tissue isalso provided, as depicted in FIG. 29. Referring to the figure, a systemfor performing transvaginal ultrasound is shown. An ultrasound probe(101) is placed inside the vagina (103) of the patient (105). A cable(107) connects the handle (109) of the probe to a monitor (111),allowing the user to visualize the ultrasound images. A typicallaparoscopic procedure is illustrated in FIG. 30. The laparoscopicapproach typically employs 2 or 3 small incisions (201), through whichvarious imaging and surgical tools (203) can be introduced. Imaging isperformed with a laparoscope (205), which allows for directvisualization of tissues. The abdominal cavity is filled with gas (207)to expand the field of view and allow for manipulation of tissues.

I. METHODS

Disclosed herein are various methods for manipulating the ovariantissues of a patient. Manipulation of the ovarian tissues may occur bymechanical manipulation of the tissues, by delivery of chemical,biologic or pharmaceutical agents, cooling/cryotherapy, or by deliveryof energy to the tissues. Although the ovarian tissues may be accessedusing any suitable approach, the methods described here generally use atransvaginal approach. The type of approach utilized may depend onfactors such as a patient's age, comorbidities, need for otherconcomitant procedures, and prior surgical history. Furthermore, in someinstances it may be desirable to provide protective elements and/orspacing devices configured to spare or separate non-target tissues, orto prevent excessive damage to the tissues. In some cases, for examplethermal treatment, the protective element can be the use of atemperature sensor (e.g. a thermocouple or thermistor), and/or an activecooling member (e.g., internally cooled electrode, irrigated electrode,irrigated guide/docking device, etc., if heat is generated). Embodimentsof spacing devices may include mechanical features incorporated into anapparatus and/or fluid infusion into the region proximate to the ovary(e.g., the peritoneal space). In some embodiments, the aspiration andirrigation functions are performed via the same lumen within theapparatus.

In one variation, the method includes accessing a target regionproximate an ovarian tissue within the patient; advancing an ovariantissue apparatus to the target region, the ovarian tissue apparatuscomprising a docking device and one or more therapeutic elements, thedocking device comprising a proximal end, a distal end, and a distaltip; contacting the ovarian tissue with the docking device; anddeploying the one or more therapeutic elements on or within the ovariantissue.

The docking device of the ovarian tissue apparatus may be advanced usingimage guidance. Image guidance may be accomplished using techniques suchas but not limited to, transvaginal ultrasound, transabdominalultrasound, endoscopic visualization, direct visualization, computedtomography (CT), or magnetic resonance imaging (MRI), optical coherencetomography (OCT), an ultrasound element on the device, virtualhistology, or a combination thereof. In some embodiments, for examplealternatively or in conjunction with image guidance, advancement andnavigation of the docking device may he accomplished using a steeringmechanism at least partially disposed within the distal end of thedocking device. For example, one or more steerable wires may he disposedwithin the docking device running from the proximal end to the distaltip of the device. Actuation of the steerable wires may occur bymanipulation of a mechanism on a handle at the proximal end of thedocking device. In some embodiments, the docking device comprises aflexible distal end, or one or more flexible segments to aid withnavigation to the target ovarian tissue. In other embodiments, thedocking device comprises a rigid member, which may have a sharpened tip.Proximal portions of the docking device may be reinforced, e.g., with abraided shaft, material of increased durometer, to provide improvedpushability and torque control.

The ovarian tissue may be engaged in various different ways. In somevariations, the step of contacting comprises applying vacuum to theovarian tissue using the distal tip of the docking device. In othervariations, the step of contacting comprises releasably securing one ormore attachment elements to the ovarian tissue. The attachment elementsmay comprise any suitable element capable of releasably securing ovariantissue. Embodiments of such attachment elements include a hook, needle,barb, or combination thereof. When vacuum is used to help engage thedocking device to a polycystic ovary, the vacuum may also be used toaspirate fluid from one or more cysts. Aspiration of cyst fluid mayreduce the size of the cyst or reduce the total number of cysts on theovary. By reducing the size of the cyst, the tissue may be drawn closerto or into contact with the therapeutic element(s), which may allow forimproved targeting of tissue (e.g., thecal cells) and/or shortertreatments times. Aspiration of fluid may also aid in the assessmentthat bleeding has been controlled after delivery of the therapy.

According to some embodiments described herein, which may partially oras a whole combine with other embodiments, the distal end of the dockingdevice comprises a tissue engagement element, and the ovarian tissue iscontacted using the tissue engagement element. In some embodiments, thetissue engagement element comprises a preformed shape, e.g., apredetermined curvature. The preformed shape may conform to the shape ofthe ovarian tissue, and aid in the deployment of the treatment elementsfrom the docking device. One or more therapeutic elements may bedeployed from the docking device on, into, or proximate to the ovarianor mesovarian tissue. When the ovarian tissue is an ovary, the size ofthe ovary may range from about 3 to 7 cm in length, about 1 to 4 cm inwidth, and about 0.5 to 4 cm in thickness. Ovaries stimulated bypharmaceutical agents such as gonadotropins may often be larger.

According to embodiments described herein, which may partially or as awhole combine with other embodiments, the therapeutic element maycomprise one or more of the following: a radiofrequency energy element;a direct heating element; a cryoablation element; a cooling element; amechanical disruption element; laser; a microwave antenna; an unfocusedultrasound element; a partially-focused ultrasound element; a focused(HIFU) ultrasound element; and/or means for delivering heatedwater/saline, steam, a chemical ablation agent, a biologic, orpharmaceutical agent, implantable pulse generator, a passive or active(e.g., electronic drug delivery unit) drug-eluting implant, aradioisotope seed, or a mechanical implant, Which may be either passiveor active via application of remote energy (e.g., ultrasound to inducevibration). In some embodiments, the therapeutic element comprises aradiofrequency energy element, e.g., a radiofrequency electrode. In someembodiments, the therapeutic element may comprise one or more curvedneedle electrodes. Additionally or alternatively, the therapeuticelement may comprise one or more straight or curved wire electrodes.According to embodiments described herein, which may partially or as awhole combine with other embodiments, the therapeutic element maycomprise one or more active electrodes on an elongate body. Here areturn electrode may be provided on the distal end of the dockingdevice, or be deployable from the docking device. Alternatively, areturn electrode may be placed on the outside of the patient. Forexample, in one variation, a return electrode may be affixed to theultrasound probe proximate the transducer. In another variation, areturn electrode may be incorporated into a needle guide. In the case ofa plurality of electrodes, any pair may be activated in a bipolar manneror individually via a return electrode. With regards to the use of thevarious types of ultrasound, it could include variations that useultrasound to create thermal heating or non-thermal ultrasound to induceacoustic cavitation.

Mechanical disruption elements could include mechanical disruption ofone or more target tissues (e.g., medulla, cortex, nerves, cysts, etc.).The mechanical disruption may include rnorcellating, tearing,compressing, stretching or otherwise destroying tissue or causing it toalter its function (e.g., induce apoptosis, trigger increased bloodflow, trigger a healing response, trigger maturation of oocytes, ortrigger ovulation). Injured/destroyed tissue may be removed mechanicallyor left within the body, allowing the body's natural healing process toresorb the destroyed tissue. The morcellated tissue may also beretrieved in some instances if it can be used for diagnosis, or ifcomponents of the removed tissue (e.g., oocytes or cellular factors) maybe useful in further care. Pharmacologic or biologic agents could bedelivered either as a one-time delivery, part of a slow-releasepreparation, or implanted as a part of a biodegradable ornon-biodegradable device. These agents could also be implanted within acasing (e.g., an electronic drug delivery unit) configured to remotelycontrol delivery of the casing's contents using a controller external tothe body. Exemplary biologic or pharmacologic agents that could beemployed include without limitation: beta-blockers, anti-androgens(e.g., finasteride, flutamide, nilutamide, bicalutamide, spironolactone,cyproterone), follicular stimulating hormone, luteinizing hormone, otherhormones, neurotoxins or tissue toxins (e.g., botox, guanethidine,ethanol), 5-alpha-reductase inhibitors e.g., finasteride, dutasteride,izonsteride, turosteride, and epristeride), insulin modulating agents,aromatase inhibitors (e.g., letrozole, exemestane, anastrozole), VEGFmodulating agents, agents modulating inhibin, agents modulatinginterleukins, pluripotent or multipotent stem cell preparations, orcellular components. Furthermore, an agent (e.g., radiopaque material,echogenic material, etc.) may be left behind to tag the location(s) inwhich the therapeutic agent(s) are delivered.

In one variation, one or more therapeutic elements are advanced on orinto an ovary. In another variation, the one or more therapeuticelements are advanced on or into an ovarian cyst. The one or moretherapeutic elements may also be advanced from the mesovarium on or intoan ovary or an ovarian cyst. In one variation, the one or moretherapeutic elements are delivered to multiple, predetermined areas onor within the ovarian tissue. In other instances, a pattern of treatmentis delivered on or into the ovarian tissue. These patterns of treatmentwithin the tissue could be linear, curvilinear, helical, interrupted,continuous, arbor-like (e.g., with a trunk and multiple offshoots), ormay comprise other suitable patterns. The therapeutic elements may beutilized such that multiple treatments may be delivered through a singleouter entry point in the ovary. The therapeutic elements may bedelivered to treat any suitable medical condition of the femalereproductive anatomy, and may be particularly beneficial in thetreatment of polycystic ovary syndrome.

Some variations of the method deliver thermal energy to the ovariantissues. The thermal energy may increase the temperature of the ovariantissue (e.g., by heating) and/or ablate/coagulate and/or desiccate/charthe tissue. The thermal energy may also be delivered to reduce thetemperature of the ovarian tissue (e.g. by cooling) or may cryoablatethe tissue. Mechanically disrupting the ovarian tissues with the one ormore therapeutic elements is also contemplated. For example, a steerabledevice could be used under image guidance to maximize the number ofovarian cysts that are ruptured as it was advanced in a path through theovarian tissue, this could be done alone or in combination with someform of thermal energy. The mechanically disrupting portion of thedevice could rupture a cyst, then imaging could identify rupturing asubsequent cyst, and the process could be repeated.

Methods useful in treating PCOS may include advancing an ovarian tissueapparatus proximate a polycystic ovary within a patient, the ovariantissue apparatus comprising a docking device and one or more therapeuticelements, the docking device comprising a proximal end, a distal end,and a distal tip; deploying the one or more therapeutic elements fromthe docking device proximate to or within an ovarian cyst; andmanipulating the polycystic ovary or ovarian cyst to effect a change inthe ovarian cyst, one or more symptoms or physiological parametersindicative of polycystic ovary syndrome, or a combination thereof. Animplantable pulse generator could be used to apply periodic electricenergy to modulate the neurohormonal environment of the ovary. Theimplantable pulse generator could be used to deliver energy proximate tovarious ovarian structures (e.g. cortex, stroma, nerves, mesovarium). Insome variations of the method, the one or more therapeutic elements aredeployed from the docking device proximate to or within an additionalovarian cyst. When the polycystic ovary or ovarian cyst is manipulated,symptoms such as infertility, anovulation, acne, obesity, abdominalpain, hirsutism, or psychological symptoms may be treated or improved.Physiological parameters of the patient that can be affected bymanipulation of the polycystic ovary or ovarian cyst may includeandrogen levels, number or size of ovarian cysts, size of the ovary,levels of anti-miillerian hormone (AMH), sex hormone binding globulin,level of luteinizing hormone (LH), ratio of luteinizing hormone (LH) tofollicular stimulating hormone (FSH), lipid levels, fasting bloodglucose, fasting blood insulin levels, response to oral glucosetolerance testing, blood glucose level, or measures of sympatheticnervous system activity (e.g., microneurography, norepinephrinespillover testing, or heart rate variability). In one aspect of the PCOStreatment described herein, a test of physiologic parameters can beperformed pre-procedurally, peri-procedurally or post-procedurally toguide therapy and/or confirm clinical success of the treatment.

The ovarian tissue apparatus, including the docking device, may beadvanced transvaginally, laparoscopically, percutaneously, via a naturalorifice route through the vagina-uterus-fallopian tubes, through an opensurgical approach, or via an entirely non-invasive approach. The stepsof advancing, deploying, and manipulating may be accomplished usingimage guidance, including but not limited to transvaginal ultrasound,transabdominal ultrasound, endoscopic visualization, directvisualization, computed tomography (CT), or magnetic resonance imaging(MRI), optical coherence tomography (OCT), an ultrasound element on thedevice, virtual histology, or a combination thereof. In the case of anentirely non-invasive approach, the steps may include positioning animaging and/or therapeutic element on the abdomen of a patient,identifying target tissue, targeting said tissue, and applying energy(e.g., partially-focused or focused ultrasound). Hybrid approaches mayalso be utilized. For example, transvaginal ultrasound may be used forimaging and/or targeting, while an external therapeutic element coulddeliver energy. Further, having ultrasound visualization in both thevagina and on the abdomen may enhance targeting.

Alternatively, or in conjunction with image guidance, and as previouslydescribed, advancement and navigation of the docking device may beaccomplished using a steering mechanism at least partially disposedwithin the distal end of the docking device. For example, one or moresteerable wires may be disposed within the docking device running fromthe proximal end to the distal tip of the device. Actuation of thesteerable wires may occur by manipulation of a mechanism on a handle atthe proximal end of the docking device. In some embodiments, the dockingdevice comprises a flexible distal end, or one or more flexible segmentsto aid with navigation to the target ovarian tissue. Proximal portionsof the docking device may be reinforced, e.g., with a braided shaft,material of increased durometer, to provide improved pushability andtorque control.

The docking device may use a docking mechanism such that a portion ofthe device arrives proximate to or to engages the polycystic ovary, anovarian cyst, or the mesovarium. In some embodiments, the dockingmechanism includes the application of vacuum to the ovarian tissue usingthe distal tip of the docking device. Alternatively or additionally, thedocking mechanism comprises releasably securing one or more attachmentelements to the polycystic ovary. The attachment elements may compriseany suitable element capable of releasably securing the polycysticovary. Exemplary attachment elements include a hook, needle, barb, orcombination thereof. When vacuum is used to help engage the dockingdevice to a polycystic ovary, the vacuum may also be used to aspiratefluid from one or more cysts. Aspiration of cyst fluid may reduce thesize of the cyst or reduce the total number of cysts on the ovary.Aspiration may be used prior to, during, or after delivery of thetherapeutic element so that the therapeutic element is more proximate totarget tissue. Aspiration of fluid may also aid in the assessment thatbleeding has been controlled after delivery of the therapy. Theaspirated fluid could also be collected and analyzed for anotherpurpose.

In some embodiments, the distal end of the docking device comprises atissue engagement element, and the polycystic ovary is contacted usingthe tissue engagement element. In some instances, the tissue engagementelement comprises a preformed shape, e.g., a predetermined curvature.The preformed shape may conform to the shape of the ovary, and aid inthe deployment of the treatment elements from the docking device.

In some embodiments, the guiding/docking device and the therapeuticelement are combined into a single entity. In other embodiments, theguiding/docking device and the therapeutic element are different but thetwo are used in tandem to deliver therapy (e.g., the guiding/dockingdevice has a therapeutic element such as an electrode that may be usedin combination or separate from other deployed therapeutic elements.Alternatively, the electrode located on the guiding/docking device maybe used as a neutral electrode with little/no therapeutic effect (e.g.,heat).

In some aspects, the methods employed herein include using adocking/guiding device to penetrate the ovary and permit delivery of oneor multiple therapeutic elements out of one or more apertures in theguiding/docking device. In some embodiments, the docking/guiding devicemay comprise, for example, a needle, and the therapeutic element maycomprise, for example, a shaft one electrode or a plurality ofelectrodes. In some embodiments, the shaft may be straight, but in otherembodiments, the distal portion of the shaft may be processed to have apre-set shape. The therapeutic element may be insulated along themajority of its length or a discrete portion(s) of its length toelectrically isolate it from the (locking device. In some embodiments,the electrodes may wrap around the entire circumference of the shaft ormay only cover a portion of the shaft circumference in otherembodiments. In each of the embodiments described in the presentdisclosure, the electrodes could be electrically isolated from eachother and deliver energy in a monopolar or bipolar fashion. Monopolarconfigurations may allow for simpler device configuration, but theyrequire a neutral electrode. Bipolar configurations may allow for energyto be contained within a more limited field of tissues. When a bipolarmethod is used, one electrode would serve as the active electrode andanother electrode would serve as the return electrode. In furtherembodiments, multiple electrodes could deliver energy and the energywould return to a neutral electrode located elsewhere, such as on theskin of the patient, on the docking/guiding device, or on the ultrasoundprobe. In some embodiments, the electrodes could also be electricallyconnected to each other and deliver energy where the return or neutralelectrode ⁻is located elsewhere, such as on the skin of the patient, onthe docking/guiding device, or on the ultrasound probe. Placing theneutral electrode on the outside of the patient (e.g., skin) may allowfor a simpler device configuration. Placing the neutral electrode on thedocking/guiding device or the ultrasound transducer may help confine theenergy delivery to a smaller field and also change the diagnosticinformation collected by impedance measurements. As shown in FIG. 31, adocking/guiding device (301) can be used to penetrate into the ovary(303) and deliver a single therapeutic element (305) out of the distalend (307) of the docking/guiding device (301). Here the therapeuticelement is delivered from the docking device at an angle away from thetrajectory of the docking/guiding device but within the two-dimensionalplane of an ultrasound field. Docking/guiding device (301) may comprisea needle and the therapeutic element (305) may include a curved shaftwith two electrodes (309) disposed thereon. The electrodes (309) may becomprised of metallic bands, coils, wires (e.g., wound or braided),laser cut tubing, or slotted tubular structures. They may wrap entirelyaround the circumference of the therapeutic element shaft (305) and maybe separated by discreet insulated areas (311). Additional detailrelating to these devices and similar embodiments is provided below.

One or more therapeutic elements may be deployed from the docking deviceon or into the polycystic ovary, proximate to or into an ovarian cyst,proximate to or into the mesovarium, or other target structure. The oneor more therapeutic elements may also be advanced from a single dockinglocation or multiple docking locations on or within the polycystic ovaryor an ovarian cyst; or advanced from a single docking location ormultiple docking locations proximate to an ovarian cyst, or proximate tothe mesovarium. The docking location(s) could be on the medial and/orinferior aspect of the ovary. The guiding/docking device could alsopenetrate into the ovary. In one aspect of the methods, there may be asingle entry point on the outside of the ovary (by either theguiding/docking device or the treatment element or the combinationthereof) through which multiple treatments could be delivered therebycausing less damage to the outside of the ovary and reducing the riskfor adhesion formation. In another variation, the energy is delivered tomultiple, areas on or within the polycystic ovary, an ovarian cyst,proximate to an ovarian cyst, proximate to the junction of the ovarianstroma and cortex, or proximate to the mesovarium allowing improvedtargeting or avoidance of certain tissues (e.g., nerves or vasculature).In other instances, a pattern of treatments is delivered on or withinthe polycystic ovary, an ovarian cyst, proximate to an ovarian cyst,proximate to the junction of the ovarian stroma and cortex, or proximateto the mesovarium.

Another aspect of the methods disclosed herein comprises orienting thetherapeutic element(s) with the transvaginal ultrasonic probe, which isgenerally limited to 2-dimensional (or planar) imaging. When thetherapeutic element has a non-linear geometry, e.g., if it is curved, itis desirable to maintain visualization of the therapeutic element viathe transvaginal ultrasound probe. Here the method may include settingthe orientation of the therapeutic element in plane with the ultrasonicprobe such that as the therapeutic element is maneuvered or deployed,the operator can visualize it. This may be employed via the method ofattaching the therapeutic device to the handle of the ultrasound probeand/or by employing a needle guide configured to attach to theultrasound probe and provide a unique guiding interface with theguiding/docking device. The method may also involve a means to quicklydecouple the orientation between the therapeutic element and thevisualization plane of the probe. For example, the operator may chooseto deploy the therapeutic element in one plane but then rotate theultrasound probe into another plane (without changing plane of thetherapeutic element) to verify placement or view other surroundingtissues. According to some embodiments, the coupling mechanism betweenthe therapeutic element and probe could provide a means of sliding orrotating the probe into a new orientation but then quickly realigningthe therapeutic element and probe (such that the deployed element isback in the visualization plane of the probe). In some instances, it maybe desirable to reorient the therapeutic element by exactly 180 degreesto allow for it to reach different regions of tissue in the same imagingplane.

Another aspect of the methods disclosed herein comprises enhancing thevisualization (i.e., echogenicity) of the guiding/docking device and/ortherapeutic elements while using ultrasound for visualization. Themethod may include providing a region of increased echogenicity on theguiding/docking device and/or therapeutic elements. In some embodiments,the region of increased echogenicity is a region that traps gas. In someembodiments, the region of increased echogenicity includes a roughenedsurface covered by a polymer sheath, which traps gas between the groovesof the roughened surface and the polymer sheath. The trapped gasenhances the echogenicity beyond using merely a roughened surface. Inother embodiments, gas may also be trapped by incorporating one or morelumens, pockets, or cavities within the therapeutic element and/or thedocking device. It may be useful to have enhanced echogenicity only atthe distal tip of the therapeutic element and/or docking device, whichcould aid in ensuring that it is within the desired target tissue. Forexample, enhanced echogenicity at the distal tip may help withvisualization of the tip within the ovary, and indicate that a regionproximal to the tip is contained within the ovary. It may also be usefulto have differential echogenicity of different parts of therapeuticelement and/or docking device to provide better assessment of deviceplacement. In some instances it may be useful for the therapeuticelement or a portion thereof to comprise an echogenic material havinggreater echogenicity than the echogenic material of the docking deviceor other portions of the therapeutic element.

Alternatively, the methods provided herein may include limited rotationand/or translation of the guiding/docking device and/or therapeuticelements while using ultrasound to enhance visualization. For example,rotation of plus or minus up to 20 degrees of rotation couldsignificantly improve visualization. The limited rotation may be usefulin maintaining the therapeutic elements within the ultrasoundvisualization plane (if so desired) while allowing the operator toquickly rotate the device back and forth to enhance visualization. Inother variations of the method, translation plus or minus up to 0.25 mmmay also significantly improve visualization. This subtle translationcould be achieved, for example, by allowing the operator to easily shiftthe therapeutic elements a small distance distally and proximally, suchas plus or minus up to 0.25 mm.

In another variation, the method may include enhancing the visualizationof the treatment zone. The method may be to use energy delivery settingsto ablate the tissue in a way that makes the ablated tissue appeardifferently on ultrasound. For example, it may be desirable to firstablate the tissue for approximately 5-15 seconds, followed by a shortburst of higher power to then desiccate/char the tissue. Thedesiccated/charred tissue may be more echogenic, thus enhancing thevisualization of the treatment zone. Additionally or alternatively, themethod may also involve infusing air or other echogenic gas/materialinto a target zone to mark that area. This may be done after performinga treatment to mark the zone treated so that an overlapping treatment isnot subsequently performed.

In another variation, the method may include affecting the target tissuein a fully non-invasive way. Here the method may include placement of anultrasound imaging and/or therapeutic element onto the abdomen of apatient; operatively connecting the ultrasound imaging and/ortherapeutic element to a console comprising a user interface, deliveringultrasound for imaging, targeting desired ovarian tissue, and deliveringenergy (e.g., partially-focused ultrasound, HIFU).

One aspect of the methods disclosed herein provides for pre-treatmentplanning prior to the manipulation of ovarian tissues. For example,pre-treatment planning could be provided for the treatment of PCOS,including PCOS infertility. Here the method may include the step ofperforming non-invasive imaging to map the size, morphology and locationof the ovary, the quantity and location of ovarian cysts, the locationof ovarian cysts relative to other anatomical landmarks, and/or thevolume of target tissue (e.g., stroma). Non-invasive imaging modalitiesmay include magnetic resonance imaging (MRI), computed tomography (CT),transvaginal ultrasound, transabdominal ultrasound, or a combinationthereof. The images and mapping performed may aid the care-giver inplanning the therapeutic procedure and/or guide the care-giver whileperforming therapy. The mapping procedure may yield images, annotatedimages, and/or information related to the relationship between cysts orother target tissue and other anatomical landmarks.

Another aspect of the methods disclosed herein provides for harvestingavailable oocytes in conjunction with delivering therapy. In onevariation, currently available tools and procedures may be used to firstharvest available oocytes or tissue containing immature oocytes, whichmay then be stored for later use. For example, oocytes may be harvestedusing a transvaginal approach using transvaginal ultrasound and aneedle. Alternatively, the therapy may be applied first. In yet anothervariation, the same tools utilized for providing the therapy may also beconfigured to also allow for oocyte harvesting. The therapy-providingtools may have improved features to aid in targeting, thus allowing formore oocytes to be harvested. These features may include methods forimproved targeting, such as methods for steering, engaging the ovaryand/or imaging.

II. SYSTEMS

Further described herein are embodiments of systems for manipulatingovarian tissues and/or treating PCOS, wherein one or more features fromany of these embodiments may be combined with one or more features fromone or more other embodiments to form a new embodiment within the scopeof this disclosure. The systems may include an ovarian tissue apparatusconfigured for advancement through the vaginal wall (transvaginally),laparoscopically, percutaneously, via a natural orifice route throughthe vagina-uterus-fallopian tubes, or through an open surgical approach,and proximate an ovarian tissue; and an energy generator electricallycoupled to the ovarian tissue apparatus, where the ovarian tissueapparatus typically comprises a docking device and one or moretherapeutic elements, the docking device typically comprising anelongate body having a proximal end, a distal end, a lumen extendingfrom the proximal end through the distal end, and a distal tip.

The ovarian tissue apparatus, docking device, therapeutic element, etc.,may be made from polymeric materials (e.g., PEEK, polyester, ABS,nylon), metals (e.g., stainless steel), metal alloys (e.g.,platinum-iridium), and shape memory materials (e.g., nitinol, elgiloy)all of which are known in the art, and thus are not described in detailhere. In some variations, the diameter of the elongate body of thedocking device may range from about 3 Fr (1 mm) to about 15 Fr (5 mm).In other variations, the length of the elongate body of the dockingdevice may range from about 15 cm to about 60 cm.

The docking device may be a relatively rigid member (e.g., needle,trocar) or flexible member (e.g., catheter, steerable catheter) withfeatures configured to help with engagement of ovarian tissues. Forexample, the distal tip of the docking device may include one or morereleasably securable attachment elements to aid in engaging the dockingdevice to ovarian tissues. The releasably securable attachment elementsmay comprise one or more hooks, needles, or barbs. Alternatively oradditionally, the docking device may be coupled to a vacuum source toenable vacuum-assisted engagement of the tip of the device to ovariantissue. In some embodiments, the distal end of the docking devicecomprises a tissue engagement element. The tissue engagement element mayhave a preformed shape, e.g., a predetermined curvature.

In further variations, one or more therapeutic elements are deliveredvia the docking device. According to some embodiments, the therapeuticelements may be slidably disposed within the docking device. Here one ormore ports may be disposed on the elongate body of the docking devicethrough which the slidahie therapeutic elements can be deployed into anovarian tissue. Additionally or alternatively, the therapeutic elementmay comprise a lumen for delivering a thermal fluid, such as heatedwater or saline, or a biologic or pharmacological agent such asbeta-blockers, anti-androgens (e.g., finasteride, flutamide, nilutamide,bicalutamide, spironolactone, cyproterone), follicular stimulatinghormone, luteinizing hormone, other hormones, neurotoxins or tissuetoxins (e.g., botox, guanethidine, ethanol), 5-alpha-reductaseinhibitors (e.g., finasteride, dutasteride, izonsteride, turosteride,and epristeride), insulin modulating agents, or aromatase inhibitors(e.g., letrozole, exemestane, anastrozole), VEGF modulating agents,agents modulating inhibin, agents modulating interleukins, pluripotentor multipotent stem cell preparations, or cellular components.Furthermore, an agent (e.g., radiopaque material, echogenic material,etc.) may be left behind to tag the location(s) in which the therapeuticagent(s) are delivered. The one or more ports may also be disposed onthe tissue engagement element. Additionally or alternatively, the one ormore therapeutic elements may include an electrode, a cryoablationelement, an ultrasound transducer, a laser, or a combination thereof.The therapeutic element, docking device, or separate device may alsocontain a lumen (or lumens) with suitable size to deliver a sufficientvolume of fluid, such as saline or lactated ringers solution, to fillthe abdominal cavity. This fluid could be used to help separate tissues(move non-ovarian tissues away from the ovary to reduce risk of injurywhen treating the ovary), improve ultrasonic visualization bysurrounding tissues with fluid, shift tissues into new locations forimproved visualization, provide cooling or other protection to the ovaryor neighboring tissues while treating the ovary, or promote healing ofthe ovary after the procedure is completed. In some embodiments, theinner diameter of the docking device may range from 0.25 to 3.0 mm, from0.25 to 2.5 mm, from 0.25 to 2.0 mm, from 0.25 to 1.5 mm, or from 0.25to 1.0 mm to allow suitable flow rate while infusing or withdrawingfluid from the abdominal cavity. In other embodiments, the innerdiameter of the docking device may range from 1.0 to 1.9 mm to allowsuitable flow rate while infusing or withdrawing fluid from theabdominal cavity, in other variations, the docking device or therapeuticelement could be used to aspirate fluid from within the ovary orretrieve sample fluid from the abdominal cavity to detect the presenceof substances, such as blood, intestinal (e.g., fecal matter), orbiomarkers, that provide information regarding the safety or success ofthe procedure.

According to some embodiments, the system may also comprise an energygenerator so that energy can be delivered to ovarian tissue via thetherapeutic elements. The energy generator may be configured to deliverone or more of the following: radiofrequency energy, direct heating,cryoablation, cooling, laser, microwave, unfocused ultrasound,partially-focused ultrasound, focused (HIFU) ultrasound, heatedwater/saline, or steam. In addition, the energy generator may be poweredusing a disposable battery, a re-chargeable battery, or via mains power.

Additionally or alternatively, the system may also comprise a mechanicaldrive system so that the therapeutic element rotates and/or translatesin order to disrupt and/or remove target tissue. The mechanical drivesystem may incorporate a motor, a drive train, and means for operativelyconnecting to the therapeutic element. In some embodiments, onlymechanical tissue manipulation may occur, but in others, mechanicalmanipulation may occur in series or in parallel with thermal energy as ameans to cut and/or cauterize the tissue to minimize the risk ofbleeding.

The system may further include a processor that has an algorithmoperable to run a feedback control loop based on one or more measuredsystem parameters, one or more measured tissue parameters, or acombination thereof. In any of the embodiments described herein, one ormore sensors may be included in the system and may be used to measurethe one or more system or tissue parameters. The sensors may betemperature sensors, impedance sensors, pressure sensors, or acombination thereof. The temperature sensor may be used to measureelectrode temperature. The impedance sensor may be used to measuretissue impedance. When implemented, the feedback control loop may beconfigured to modify a parameter of energy delivery based on themeasured one or more system or tissue parameters. For example, theparameter of energy delivery (or energy removal in the case ofcooling/cryotherapy) that may be modified is duration of energydelivery, power, voltage, current, intensity, frequency, pulse, pulsewidth (e.g., duty cycle), temperature, type of energy delivery, flowrate, pressure, or a combination thereof.

Any of the systems disclosed herein may further comprise a userinterface configured to allow user defined inputs. The user-definedinputs may include duration of energy delivery, power, targettemperature, mode of operation, or a combination thereof. The mode ofoperation may be a coagulation mode, a heating mode, a cooling mode, acryoablation mode, an ablation mode, a desiccate/char mode, anirrigation mode, an aspiration mode, mechanical disruption mode, tissueremoval mode, or a combination thereof. Any of the systems disclosedherein may further comprise an automated treatment delivery algorithmthat could dynamically respond and adjust and/or terminate treatment inresponse to inputs such as temperature, impedance, treatment duration,treatment power and/or system status.

According to embodiments described herein, which may partially or as awhole combine with other embodiments, the system and method may includea transvaginal ultrasound probe for placement in the vagina to aid withvisualization of tissue and/or navigation of system components. Adocking/guiding device (e.g., a docking catheter) may be coupled to theultrasound probe and advanced through the wall of the vagina directlyinto the peritoneal space to engage the surface of the ovary (e.g,, themedial aspect of the ovary), or be advanced into the ovary, underultrasound guidance. Via this docking catheter, a treatment device couldbe deployed such that one or more radiofrequency energy treatmentelements, e.g., electrodes, are delivered within the ovary through asingle entry point on the surface of the ovary. Following delivery ofthe treatments, aspiration could be applied at the aperture created inthe ovary. Aspiration could also be achieved via holes or slots in ornear an electrode that are connected to a lumen in the docking catheter.In an alternative embodiment, aspiration may be applied prior to and/orduring delivery the treatments.

In some embodiments, e.g., prior to or after docking on/engaging theovary, the system may include a spacing device that includes anexpandable structure, or that is configured to infuse fluid for creatingspace around the ovarian tissues or for separating ovarian tissues. Forexample, the spacing device may contain scaffolding,one or moreballoons, or at least one port for delivering fluid or gas into thespace adjacent to the ovary, the purpose of which would be to aid in theseparation of tissues such that the desired portion of the ovary couldmore optimally be accessed and such that therapeutic elements could bedelivered in a way to minimize disruption of non-ovarian tissues.Referring to FIG. 2, in one embodiment the spacing device (20) mayinclude scaffolding having an expanded configuration (22) and acollapsed configuration (not shown). Here the expanded configuration(22) is effected by movement of an outer shaft (24) relative to an innershaft (26). Upon motion of the outer shaft (24) relative to the innershaft (26), the scaffolding is able to transition from its collapsedconfiguration to its expanded configuration (22). Other expandablescaffolds may be constructed from self-expanding materials that areconstrained for delivery then expanded via removing the constraint. Thescaffold may be made from a polymer, metal, metal alloy, or combinationsthereof. The scaffold may also comprise one or more wires, braid, alaser cut tube, or a slotted tube.

In the embodiment shown in FIG. 3, the spacing device (30) comprises aballoon (32) that is concentrically disposed about a shaft (34). Theballoon (32) is inflated via fluid (e.g., a liquid or a gas) flowingthrough an infusion port (36) in the shaft (34).

In another embodiment, as shown in FIG. 4, the spacing device (40)includes a plurality of infusion ports (42) that may be located at thedistal end/or in one or more locations along the length of the shaft(44) for the delivery of infusate (I) to create space around targetovarian tissues or to separate ovarian tissues. In some variations, thespacing devices may be used to displace non-target tissues (e.g., bowel)during advancement of system components, e.g., docking devices, from thevagina to the ovary.

Furthermore, FIG. 5 shows an embodiment of an atraurnatic or flexiblesheath-like device (50) that may be delivered and potentially guided viaa blunt dissection element (52) and guidewire (54) or steering mechanism(not shown) through the vaginal wall and proximate to the ovary. Oncepositioned, the optional blunt dissection element (52) and/or guidewire(54) may be removed and the guiding/docking device and or therapeuticelement(s) may be delivered through the lumen of the outer sheath (56).The outer sheath (56) may serve as the guiding/docking device withoptional aspiration used to engage the ovary or infusion to createadditional space as described in association with FIG. 4. In someinstances, the guidewire (54) may be sharpened and used to penetrate theovary once the dissection element (52) is positioned proximate theovary. In this configuration, the guidewire (54) may be positioned at atarget location within the ovary. Once positioned, the dissectionelement (52) may be removed and replaced with therapeutic element(s) inan over-the-wire approach. The guidewire (54) may optionally be removedprior to applying therapy.

As previously stated, the guiding/docking device may be one component ofthe systems described herein, and could be utilized to facilitate accessto the ovaries from the selected approach. The guiding/docking devicemay have a preset shape that facilitates navigation to the ovary and itcould be torqueable. Additionally or alternatively, it could have asteerable tip that could be actuated by the handle. The guiding/dockingdevice and the therapeutic device could also be combined into a singledevice, e.g., an ovarian tissue apparatus. The docking device generallycomprises an elongate body (e.g., a needle, trocar or catheter) having aproximal end, a distal end, a lumen extending from the proximal endthrough the distal end, and a distal tip. This lumen may be used todeliver fluid and/or to aspirate.

Docking to the ovary can be accomplished using various techniques.Referring to FIG. 6, docking to the ovary (60) can be accomplished by adocking device (62) that applies vacuum (64) through a lumen of thedocking device (62). Alternatively, as shown in FIG. 7, docking to theoutside of the ovary (70) may be accomplished by a docking device (72)via a concave surface or surface that was mildly abrasive on the dockingdevice (not shown), or via one or more hooks (74) at the distal end (76)of the docking device (72) that are configured to secure to a desiredsection of the ovary (70). Instead of docking to the outside surface ofthe ovary, docking within the tissue of the ovary (80) can also beperformed, as shown in FIG. 8. Here docking may be accomplished using adocking device (82) having one or more needles or wires (84) that aredeployable through the distal end (86) of the docking device (82), andwhich are configured to anchor within the tissue of the ovary (80). Theneedles, wires, or hooks may also be configured to deliver therapy(e.g., they may be wire electrodes or may further incorporate electrodesfor delivering energy and/or may have mechanical motion applied tomechanically disrupt tissue). In some instances, it may be useful tosecure the ovary in a manner that allows for repositioning for furthertreatments. Anchoring either the docking device and/or the therapeuticelement in the target tissue may help the user to move the ovaryrelative to surrounding non-ovary tissues to improve and/or confirmvisualization. Moving the ovary may also allow the user to more easilyreposition the device for subsequent treatments.

Docking could further be accomplished using a docking device having apreset shape that is configured to fit the shape of the ovary at aspecific location. In this variation, the docking device could beconfigured to engage ovaries having a size ranging from about 3 to 7 cmin length, about 1 to 4 cm in width, and about 0.5 to 4 cm in thickness.For example, as shown in FIG. 10, docking device (102) has a shapedportion (104) at its distal end that is shaped to fit the junction ofthe ovary (106) and the broad ligament (108) (e.g., near themesovarium), and which could allow therapeutic elements (110) disposedtherein to he advanced/delivered into the ovary adjacent to themesovarium (112). The multiple therapeutic elements (110) may be curved,but their structure is not so limited, and any suitable configurationmay be employed. In one exemplary embodiment, the docking device maycomprise a cup configured to engage at least a portion of the outersurface of an ovary. Here the cup may comprise a proximal end configuredfor communication with a vacuum source and a distal end for securing theovary. The distal end of the cup can have an arcuate or annular surfaceconfigured to match the contours of the outer surface of the ovary. Thedistal end can also be sized to match the dimensions of a human ovary,wherein the distal end has a diameter of about 0.5 to 7.0 cm, about 0.5to 6.0 cm, about 0.5 to 5.0 cm, about 0.5 to 4.0 cm, about 0.5 to 3.0cm, about 0.5 to 2.0 cm, or about 0.5 to 1.0 cm. Additionally, the cupmay comprise a conical geometry for accommodating a variety of ovarysizes.

Further embodiments of the docking mechanism may include securing theovary at more than one point with a docking device. With such a device(90) as shown in FIG. 9, docking could occur at opposite sides of theovary (92), which could facilitate delivery of therapy across the entireovary or between multiple points on and/or within the ovary in a waythat either mechanically penetrates or does not mechanically penetratethe outer surface of the ovary. A docking/guiding device (90) thatgrasps at two or more places on the ovary (92) may have the ability tobe actuated or adjusted to widen or narrow the amount of ovarian tissuecaptured between its contact points. Alternatively, therapeutic elementsmay be delivered through the docking devices (90) and into the ovary(92), facilitating independent control of positioning the therapeuticelements.

FIGS. 11A and 11B depict yet further variations where thedocking/guiding device (200) could be used to target and/or capture themesovarium (202) (e.g., by looping around the mesovarium as shown inFIG. 11B) to deliver therapy to the mesovarium (202) and/or thesuspensory ligament (206) or ovarian ligaments. In this configuration,therapy may be delivered via electrodes incorporated into thedocking/guiding device (200), or via a separate element.

The therapeutic elements may have any suitable configuration, e.g., theymay have any suitable length, diameter, flexibility, geometry, shapememory, etc. suitable for the ovarian tissue procedures describedherein. In some variations, the therapeutic elements include one or morecurved structures that comprise one more electrodes. A therapeuticelement such as those depicted in FIG. 12A-12F comprising one or morecurved structures with electrodes may be useful for a variety ofreasons. The curved structure may aid in anchoring the device in thetarget tissue, limiting the risk of the device moving during treatmentdue to patient movement or user error. The curved structure may also beconfigured to match the contour of the ovary, allowing for improvedpositioning within a variety of sized or shaped ovaries. Additionally oralternatively, the curved structure may allow for longer or additionalelectrodes to be delivered and used simultaneously, allowing for largerablation volumes per energy application. This feature may limit painexperienced by the patient and reduce procedure time. The curvedstructures may have a straightened length and an unconstrained radius ofcurvature. The straightened length may range from about 5.0 to about 40mm, from about 5.0 to about 35 mm, from about 5.0 to about 30 mm, fromabout 5.0 to about 25 mm, from about 5.0 to about 20 mm, from about 5.0to about 1.5 mm, or from about 5.0 to about 10 mm. The unconstrainedradius of curvature may range from about 3.0 to about 10 mm, from about3.0 to about 9.0 mm, from about 3.0 mm to about 8.0 mm, from about 3.0mm to about 7.0 mm, from about 3.0 mm to about 6.0 mm, from about 3.0 mmto about 5.0 mm, or from about 3.0 mm to about 4.0 mm. In sonicembodiments, the unconstrained radius of curvature ranges from about 4.0mm to about 6.0 mm.

The therapeutic elements may be advanced into the ovary in various ways.For example, and as shown in FIGS. 12A-12E, upon advancement of thedocking device (300) through the capsule (316) of the ovary (304), thetherapeutic element(s) (306) are advanced from inside the ovary (304) toa target location(s) within the ovary (304). The therapeutic elementsmay be curved (FIG. 12A, 306) or straight (FIG. 12B, 308), or they maytake a spiral or helical configuration (FIG. 12C, 310) a randomconfiguration (not shown) when deployed, e.g., within an ovarian cyst(312). Alternatively, and as shown in FIG. 12D, the therapeutic element(314) may be configured to track about at least a portion of theperimeter of the ovary (304) such that therapy targets tissue proximatethe cortex or follicles of the ovary (304). Alternatively, thetherapeutic element may be configured to track about at least a portionof the ovary at or near the junction of the stoma and cortex such thattherapy may target tissue proximate to this junction. The therapeuticelements may be provided as a feature of the guiding/docking device.They may also be provided as elements that can be deployed from a lumenwithin the guiding/docking device or sheath-like device, as shown inFIG. 5. The therapeutic elements (306) may be shaped such that theyreleasably secure the device within the tissue when deployed, as shownin FIG. 12A.

The one or more therapeutic elements (306, 308, 310, 314) may beadvanced from the docking device (300) into the ovary (304) one ormultiple times and deployed within the ovary proximate to or withinovarian cysts or other target tissue. One benefit of this method may bethat multiple therapies (e.g., multiple sequential therapies where asingle therapeutic element is repositioned, or sequential/simultaneousdeployment of multiple therapeutic elements) could be delivered througha single entry/access point (302) on the surface of the ovary, which mayminimize the risk of adhesions.

FIG. 12E depicts a variation where the docking/guiding device (300) isused to penetrate into the ovary (304) and permit delivery of one ormultiple therapeutic elements (318) out of the distal tip (320) orthrough one or more side ports (322). The docking/guiding device (300)may comprise, for example, a 14 to 18 gauge needle approximately 20 to45 cm long, and the therapeutic element (318) may comprise, for example,one or more 0.020 cm to 0.076 cm diameter metal wire(s) that exit theside port (322), as shown, or the distal tip (320). However, thediameter of the metal wire may be as large as 0.140 cm. In some cases,the wire may simply be a straight wire, but in other variations, thedistal portion of the therapeutic element (318) may be processed to havea pre-set shape (e.g., a curve), as shown in FIG. 12E. The therapeuticelement may be insulated along the majority of its length toelectrically isolate it from the docking device (e.g., via a polyimidesleeve, PET heat shrink), if it is constructed of metal. As such, onlythe distal portion of the wire(s) that extend beyond the distal end orside port would be electrically connected to the energy generator. Whentwo wires are employed, they may be deployed in a geometry similar tothat shown in FIG. 12A with a distance between the tips of the wiresranging from approximately 3 to 20 mm apart. However, in other instancesthe distance between the tips of the wires may range from about 7.0 to10 mm apart, or up to about 15 mm apart.

The docking/guiding device may also be configured to rest on the outersurface of the ovary (i.e., the distal tip of the docking device is notinserted into the ovary). For example, as illustrated in FIG. 12F, thedocking device (300) may include a wider element or shelf (324) proximalto the therapeutic element (326) to act as a backstop and prevent itfrom penetrating deeper into the ovary than a preset distance. Forexample, the shelf may have a diameter greater than or equal to about20% larger than the diameter of the element to be inserted into theovary.

Referring back to FIG. 10, the side holes (114) of the guiding/dockingdevice (102) could alternatively be used to facilitate delivery of thetherapeutic elements (110) in a pre-specified consistent pattern ofmultiple entry points of the ovary. This could be done to allowconsistent targeting of a preferential portion of the ovarian tissue orto deliver a preferential pattern of therapies.

The system may also provide features that are configured to rotate theone or more therapeutic elements during application of energy tofacilitate driving the therapeutic elements through the tissue (e.g.,cutting, removing, or ablating a volume of tissue), resulting in alarger treatment zone.

The total affected volume of tissue within a given ovary may range fromabout 240 mm³ to about 3000 mm³, with a single ablation volume rangingfrom about 30 mm³ to about 3000 mm³. In some instances, about 3% toabout 20% of the ovarian volume is affected, e.g., by ablation. Thesystem may be configured such that ablations do not extend beyond acertain distance from any edge of the electrode(s), e.g., 5 mm. Thesystem may be further configured such that the ablations arenon-spherical in shape, e.g., the in-plane longest dimension is greaterthan 2 times the perpendicular depth. The system may be furtherconfigured such that ablations can be delivered within the ovary in away that spares tissue within 2 mm of the outer surface (capsule) of theovary.

Referring to the exemplary stepwise illustration in FIGS. 13A to 13D, aguiding/docking device (400) is advanced into the ovary (402) andcurvilinear therapeutic elements (404) deployed from a location insidethe ovary to a target area(s) (FIGS. 13A and 13B). The curvilineartherapeutic elements (404) are then rotated in the direction of thearrow shown in FIG. 13C to affect, e.g., ablate, a volume of tissue(FIG. 13D, 406). A variety of the therapeutic elements described hereinmay be rotated and/or translated during the application of energy toreduce force required to traverse through tissue, cut, coagulate,desiccate/char, reduce treatment time and/or create a larger treatmentzone. These techniques may be employed with other therapeutic elementsas described herein and are not limited to those shown in FIGS. 13A to13C.

The system may also provide features that are configured to move thetherapeutic elements within a single 2-dimensional plane through thetissue during application of energy to facilitate driving thetherapeutic elements through the tissue (e.g., cutting), resulting in alarger treatment zone, which is depicted in the stepwise illustration ofFIGS. 14A to 14E. Referring to FIGS. 14A to 14E, a guiding/dockingdevice (500) is advanced into the ovary (502) and curvilineartherapeutic elements (504) deployed from a location inside the ovary toa target area(s) (FIGS, 14A and 14B). The curvilinear therapeuticelements (504) are then actuated in the direction of the arrows tochange from an open configuration (FIG. 14C) to a closed configuration(FIG. 14D) to affect, e.g., ablate, a volume of tissue (FIG. 14E, 506).Although curved therapeutic elements are depicted, therapeutic elementscomprising any suitable geometry, e.g., straight therapeutic elements,may be employed. Further, it is understood that any suitable therapeuticelement described herein may be translated in a 2-dimensional plane oftissue during the application of energy to reduce force required totraverse through tissue, cut, coagulate, desiccate/char, reducetreatment time and/or create a larger treatment zone.

According to embodiments described herein, which may partially or as awhole combine with other embodiments, the therapeutic element may alsocomprise an expandable balloon that may be used to anchor the devicewithin the tissue, mechanically disrupt tissue and/or deliver thermalenergy (e.g., RF, microwave, ultrasound, direct heat) or cooling (e.g.,cold saline, cryo). In one variation, as shown in FIG. 15A, a balloon(600) is mounted on the guiding/docking device (602). In anothervariation, as provided in FIG. 15B, the balloon (600) is deliveredthrough the guiding/docking device (600) by pushing it out. In a furthervariation, the guiding/docking device may be advanced through theovarian tissue to create a channel into which the balloon is deliveredas the guiding/docking device is subsequently retracted. One or moreelectrodes, antennae, or ultrasound transducers may be positioned withinthe balloon or on the balloon surface to induce heating of tissuedirectly and/or indirectly. Alternatively, a cold or cryogenic materialmay be delivered and removed/outgassed via lumen(s) within theguiding/docking device to induce cooling or freezing of tissue,

FIG. 31 depicts another embodiment of a docking/guiding device having asingle therapeutic element. Here the docking/guiding device (301) maycomprise, for example, a 14 to 18 gauge needle approximately 20 to 45 cmlong, and the therapeutic element (305) may comprise, for example, acurved shaft having a diameter of about 0.05 cm to about 0.13 cm and twoelectrodes disposed thereon, as shown. The shaft may have a pre-setshape (e.g., a curve with radius 0.38 cm to 1.6 cm). The therapeuticelement may be insulated along the majority of its length toelectrically isolate it from the docking device (e.g., via a polyimidesleeve, PET heat shrink, Parylene, nylon, Pebax), if it is constructedof metal. As such, the uninsulated portions would be electricallyconnected to the energy generator. In another variation, therapeuticelement may be comprised of a non-electrically conductive shaft with oneor more electrically conductive elements, e.g., electrodes. Aspreviously described, the electrodes may wrap around the entirecircumference of the shaft or may only cover a portion of the shaftcircumference, in which case the electrodes may or may not be angularlyoffset from one another, The electrodes could be electrically isolatedfrom each other and deliver energy in a monopolar or bipolar fashion. Ina bipolar configuration, one electrode would serve as the activeelectrode and the other electrode would serve as the return electrode.In another variation, both electrodes could delivery energy and theenergy would return to a neutral electrode located elsewhere, such as onthe skin of the patient, on the docking/guiding device, or on theultrasound probe. The electrodes could also be electrically connected toeach other and deliver energy where the return or neutral electrode (notshown) is located elsewhere, such as on the skin of the patient, on thedocking/guiding device, or on the ultrasound probe. The electrodes mayhave a length of about 0.10 cm to about 2.5 cm; a diameter of about 0.05to about 0.4 cm, about 0.05 to about 0.3 cm, about 0.05 to about 0.2 cm,about 0.05 to about 0.1 cm, about 0.2 to 0.4 cm, or about 0.076 cm to0.14 cm; and spacing of 0.050 cm to 0.64 cm.

Other systems and methods may be employed for treating polycystic ovarysyndrome, as illustrated in FIGS. 16A to 16D. For example, theguide/docking device (700) may be advanced thorough the ovary (702) ineither a straight path (FIG. 16B) or in a meandering/directed path (FIG.16A). This could be done under imaging to ensure that theguiding/docking device (700) was placed in a desirable locationthroughout the delivery. The therapeutic element (706) could then bedelivered through a lumen on the guiding/docking device (700) and into acyst (708) and/or channel (710) created by the guiding/docking device asit was retracted. Aspiration could be performed by the guiding/dockingdevice (700) as it is being delivered or retracted. Alternatively,aspiration could also be performed through the therapeutic element(706). Alternatively, no aspiration could be performed. Once fullydeployed, the position of the entire therapeutic element (706) can beconfirmed in real-time using 2D or 3D imaging (e.g., transvaginalultrasound), allowing for all planned treated areas to beassessed/confirmed prior to application of energy. If desired, thetherapeutic element may be recaptured and re-deployed to optimizeposition. Then, energy may be applied via the therapeutic element, whichis electrically coupled to an energy generator. Optionally,theguide/docking device (700) and therapeutic element (706) can beretracted to the next desired treatment location, and energy applied.This optional step may be repeated until all desired treatments areperformed, resulting in a treated section. Alternatively, and as shownin FIG. 16D, a longer portion of the therapeutic element (706) can beexposed to multiple regions of the ovary by an extended retraction ofthe guiding/docking device (700). The treated section may be created bya single application of energy over the length of the therapeuticelement, multiple applications of energy over portions of thetherapeutic element, or by continuously applying energy whilesimultaneously retracting the guide/docking device (700) and/ortherapeutic element (706). The exemplary therapeutic element (706) usedin this instance could be an expandable mesh. FIG. 17 depicts analternative therapeutic element comprised of a flexible wire, cable, orcoil (800). The expandable mesh material may enhance or maximize contactwith tissue, especially within a cyst. Another example of a therapeuticelement that could be used in this setting is a balloon (e.g., as shownin FIGS. 15A and 15B). Any of the other therapeutic elements disclosedherein may also be utilized to administer treatment via this method. Thetherapeutic element may also have an atraumatic tip.

In the case of mechanical disruption, the therapeutic element maycomprise a rotating or translating element capable of mechanicallymanipulating (e.g., destroying, stimulating) target tissue, asillustrated in FIGS. 18A to 18D. Here the tip (900) of a guiding/dockingdevice (902) may be used to facilitate access into the ovary (904). Oncepositioned in a desired location within the ovary (904), a mechanicaldisruption element (906, 908) may be advanced in the direction of arrow(910) into the tissue. Once deployed, the mechanical disruption elements(906, 908) may be rotated in the direction of arrows (912) and/ortranslated in the direction of arrows (914) to disrupt tissue. Motion ofthe therapeutic element may be performed manually via a handle at theproximal end of the device or via a motor and/or drive train (battery ormains powered). Mechanical disruption elements may take the form of asolid screw-like component (906), an expandable wireform component(908), or other geometry that facilitates desired tissue disruption. Theexpandable wireform component (908) may be comprised of a self-expandingmaterial (e.g., spring steel, nitinol, elgiloy) that expands as tissueis morcellated. The therapeutic element may also incorporate one or moreelectrodes used to delivery energy to heat target tissue, ablate targettissue, cauterize blood vessels, and/or cut tissue. The morcellatedtissue may be retrieved in some instances if it can be used fordiagnosis, or if it contains either oocytes or cellular components thatmay be useful in further care. Electrodes may be either separateelements mounted on the therapeutic element or the therapeutic elementitself.

The therapeutic element(s) may be constructed from a variety ofmaterials and in a variety of geometries. In its simplest form, thetherapeutic element may be comprised of round wire. Alternatively, asshown in FIG. 19, the therapeutic element (1000) may be disposed at thedistal end (1002) of a guiding/docking device in a manner such that itis capable of expanding upon deployment. In some embodiments, thetherapeutic element (1000) may be constructed of a metal tube or wire(e.g., nitinol, elgiloy, spring steel) with characteristics that allowfor it to be shaped into an expanded configuration (1006) and acollapsed configuration (1008), and to form a sharp end (1010). Themetal tube or wire may be laser cut or otherwise processed to split thetube or wire in half along a defined length (1012), which may, forexample, range from about 1-3 cm. The metal tube or wire may further becut, ground or otherwise processed to form a sharp end (1010). Once cut,the two (as shown) or more therapeutic elements may be shape set orformed into an expanded configuration (1006). When constrained by asheath (1004), the distal end is collapsed, and an exposed portion ofthe sharp end (1010) used to penetrate the tissue and position thedevice. Once in position, the therapeutic element (1000) may be advancedout of the sheath and expanded into the tissue. Alternatively, the outersheath (1004) may be retracted to allow the therapeutic element (1000)to become exposed. In some instances, additional manipulation and/orapplication of energy may be required to facilitate expansion of thetherapeutic element. Energy may simultaneously or sequentially beapplied to affect the target tissue. These techniques may also beemployed with the variety of therapeutic elements described elsewhereherein.

FIGS. 20A to 20C depict embodiments of exemplary light-based therapeuticelements that may be used to heat or ablate target tissue. FIG. 20Ashows a fiber optic approach where a light fiber (2000) is deployed fromthe distal end of a guiding/docking device (2002), shown here as aneedle. Once the light fiber (2000) is positioned proximate the distalend (2004) of the guiding/docking device (2002), it may be activated togenerate heat within the target tissue. The light fiber (2000) may berepositioned and activated in multiple locations to complete thetherapy. In some cases, it may be desirable to extend the light fiber(2000) beyond the distal end (2004) of the guiding/docking device (2002)up to about 1 cm. In other cases, it may be desirable to recess thelight fiber (2000) proximal to the distal end (2004) up to about 5 mm.

FIG. 20B shows another variation where light (2006) from one or morelight fibers (not shown) exits the side of the guiding/docking device(2002) via holes (2008), once positioned, the individual light fibersmay be activated one at a time, in pairs, in groups, or allsimultaneously. Further, all fibers may activate at the same ordifferent power levels. Depending on the configuration, the energydistribution around the circumference of the guiding/docking device(2002) may be symmetric/concentric or asymmetric/eccentric.

In some variations, the same light fiber(s) used to deliver energy mayalso be configured to measure temperature via operatively connecting thefiber to an IR temperature sensor. The light fiber may then switch backand forth or multiplex in order to intermittently monitor temperatureduring the treatment.

FIG. 20C shows an alternative light-based device where a laser diode(not shown) and prism (2010) are used to deliver energy to the targettissue. In this case, the laser diode may be located anywhere proximalto the prism (2010), which is located near the distal end of theguiding/docking device (2002), depicted as a needle in this example.Once activated, the prism (2010) may direct the energy out one or moreside holes (2012) to generate the desired heat within the target tissue.If the laser wave length were extended into the infra-red range (e.g.,≥800 nm), then light absorbing dyes could be used to increase the rangeor size of affected tissue. Such dyes may be injected at the sitethrough a lumen in the guiding/docking device (2002) just prior toactivating the laser.

The therapeutic elements may also include multi-polar embodiments, asshown in FIGS. 21A to 21B. Multi-polar electrode approaches would havethe effect of increased flexibility and/or control over lesionformation. Since each electrode can be controlled independently, eachmay also be capable of monitoring tissue characteristics (e.g.,impedance or temperature). These characteristics may be used by thecontroller and/or user to adjust the application of energy to optimizetherapy and/or provide safety shut-offs. For example, if the temperatureof two electrodes is lower than a pre-specified target and the other twoelectrodes are at or above said pre-specified target, the controller mayincrease the power level to those two electrodes to increase the tissuetemperature at those two electrodes. FIG. 21A depicts a multi-filarconfiguration where multiple (e.g., four) electrodes (3000) are spacedaround the circumference of a guiding/docking device (3002) with a layerof insulation or insulative jacket (3004) (e.g., PET heat shrink)between the electrodes (3000) and the guiding/docking device (3002).Herein the guiding/docking device (3002) is constructed from metal(e.g., a 14 to 18 gauge needle). The electrodes (3000) consist ofindividual conductive wires that are adhered to the insulative jacket(3004) and extend along the length of the guiding/docking device (3002)and are electrically isolated from one-another via an insulative jacket(3006) (e.g., PET heat shrink) along the proximal shaft. In thisconfiguration, the active length of each electrode may range from about3 mm-15 mm, and the diameter of each electrode may range from about0.012 cm-0.026 cm. In an alternative embodiment each conductive wire maybe individually insulated along the proximal length with insulationremoved along the distal portion to form the electrodes. Theseelectrodes may be energized, for example, in a monopolar or bipolar(e.g., 90° or 180° apart in a four electrode configuration) fashion.

In yet a further variation, as shown in FIG. 21B, multiple (e.g., four)circumferential electrodes (3008) are positioned around theguiding/docking device (3002) with insulative layers similar to thosedescribed in FIG. 21A. In this configuration, the electrodes may becomprised of metallic bands, coils, or wires and may be spaced apart byabout 3 mm-5 mm. These electrodes may be energized, for example, in amonopolar or bipolar (e.g., adjacent or alternating pairs) fashion.

The energy delivery element may also comprise a bipolar coaxial needledevice, as depicted in FIG. 22, where the outermost element is thereturn electrode (4000), which in this variation consists of a 16 to 18Gauge hypodermic tube insulated on the outside with a layer of polyestershrink tubing or other non-conducting material (e.g., parylene)(4002).The insulating layer begins at a specified distance, L1, from the distalend (4010) and extends fully proximal. Inside the outermost element isthe active electrode (4006), consisting of either a solid shaft orhollow tube, with an insulating layer (4008) beginning a specifieddistance, L2, from the distal tip (4004) and extending fully proximal.L1 and L2 may range from approximately 2 to 8 mm. In some instances, thedistance between the two electrodes is fixed, but in others, it may beadjustable. If adjustable, the generator may be configured to detectchanges in the distance and display recommended power settings orautomatically adjust power settings based on detected distance. By wayof example, should the distance increase, the power and/or time may beincreased. Alternatively, there may be a mechanical indicator at or nearthe proximal end of the device (e.g., incorporated into the handle) thatshows the distance along with the recommended power level. In this case,the operator would then manually set the power via the user interface onthe generator. If the return electrode (4000) is significantly largerthan the active electrode (4006), bipolar application of energy mayresult in substantial heating of the active electrode with minimal or noheating of the return electrode. This would allow for a single lesion tobe generated proximate the active electrode without the need for aseparate neutral electrode placed on the patient's skin. It would alsoallow for the neutral electrode to monitor tissue characteristics incontact with it, which may be used as an indicator of when to ceasetreatment example, the active electrode may heat tissue via resistiveand/or conductive heating until the neutral electrode detects anincrease in temperature or impedance. The system may then ceaseapplication of energy should a pre-set or user-controlled threshold bereached. If the distance between the electrodes is adjustable, itprovides the advantage of user adjustability. For example, if thepatient has a very large ovary, the user may choose to position theelectrodes further away from each other to generate a larger lesion,thus reducing procedure time. In this instance, both electrodes may beapproximately the same size, such that they both heat the tissue andpotentially create a continuous lesion between them via resistive and/orconductive heating.

As previously stated, the therapeutic elements may consist of one ormore of the following: a radiofrequency energy element; a direct heatingelement; a cryoablation element; a cooling element; a mechanicaldisruption element; a laser/light; a microwave antenna; an unfocusedultrasound element; a partially-focused ultrasound element; a focused(HIFU) ultrasound element; and/or means for delivering heatedwater/saline, steam, a chemical ablation agent, a biologic orpharmaceutical agent, a drug-eluting implant, a radioisotope seed, or amechanical implant, which may be either passive or active viaapplication of remote energy (e.g., ultrasound to induce vibration).There may be mechanical methods built into the device design to preventthe therapeutic element from being advanced more deeply than apredetermined depth.

If energy is being applied via one or more electrodes or elements, itmay be applied in a monopolar, bipolar, or combined fashion; eachelement may fire simultaneously or sequentially; energy may be appliedin a continuous or pulsed fashion, and the system may have a userinterface (FIG. 23, 5010) that allows the user to choose whichelectrodes or elements are active to customize the therapy for eachpatient. Different combinations of electrodes could be used to deliverenergy such that patterns of treatment are achieved. For example, oneembodiment could contain three electrodes (A, B, C). Any or all threecould deliver energy in a monopolar fashion and/or any combination ofelectrodes could also deliver energy in a bipolar fashion (e.g., A to B,B to C, A to C). Energy delivery could alternate in pulses (mono A,followed by mono B, followed by mono C, followed by bipolar A to B,bipolar B to C, etc.). Or, different frequencies of energy could bedelivered simultaneously or sequentially (e.g., mono at 465 kHz andbipolar at >1 MHz). These combinations may also be used for tissuemapping prior to or during the delivery of therapy. A monopolarapplication of energy would have the effect of generating a treatmentarea adjacent to the electrode and may be used to generate largerlesions at higher power in shorter time, relative, to a bipolarapplication. A bipolar application of energy would have the effect ofgenerating a treatment area adjacent to each electrode with thepotential to create a continuous lesion spanning the volume between theelectrodes via either resistive or conductive heating. A bipolarapplication of energy may also allow for lower power and smallerlesions. In addition, a bipolar application of energy may also allow fortissue characteristics (e.g., impedance, temperature) to be monitored ateach electrode and adjustments made either before (e.g., user or systemselected based on tissue characteristics, such as impedance, or based onelectrode position) or during treatment (e.g., switching which electrodeis active versus the return). A combined application of both monopolarand bipolar energy would also have the effect of generating a treatmentarea based upon tissue characteristics monitored at each electrode orbetween pairs of electrodes (e.g., impedance, temperature) with theadded ability to use a single electrode, if appropriate. In thisinstance, the return electrode may be outside the ovary or on the skinof the patient. A continuous application of energy may have the effectof generating a lesion via a combination of both resistive andconductive heating. Application of energy in a pulsed fashion wouldlimit the amount of conductive heating and may allow for additionalmeasurements to be made between pulses, when energy is turned off orreduced to a lower power. These additional measurements may then be usedto alter or cease the application of energy and/or to provide additionalfeedback to the user. The use of different frequencies may allow forreduced or increased electrical coupling between multiple conductors(e.g., wiring) or electrodes. In the case of tissue mapping, the use ofdifferent frequencies may elicit different responses from differenttypes of tissues and/or different states of tissues (e.g., ablatedtissue or unablated tissue). Furthermore, in the case of ablationcreation, the use of different frequencies may create different lesioncharacteristics.

A generator is generally included in the systems described herein tocreate energy to be delivered through the therapeutic element(s). Thesystems may include sensing elements on either the therapeutic elementand/or on the guiding/docking device to detect parameters such astemperature, impedance, or other parameters that could guide therapydelivery. A feedback control system may use detected parameters withinsoftware algorithms such that treatment is delivered automatically andcould be automatically stopped when certain temperature, time, powerand/or impedance thresholds have been crossed. The system could alsodeliver two or more different sets of energy parameters. For example, tothe system could be configured to deliver lower energy or temperaturefor a longer time (e.g., to ablate and/or otherwise affect a largervolume of tissue) and higher energy or temperature for a short time(e.g., to control bleeding and/or desiccate/char tissue to enhancevisualization). The parameters of the therapeutic element or the patternof the targeting within the ovary could be configured to preferentiallytarget certain regions and/or tissues and spare others. The sensingelements could also be used before treatment is applied to characterizeor map the target tissue; for instance, impedance measures could be usedto sense if the docking/guiding device and/or therapeutic element isadjacent or within cysts, to sense if portions the docking/guidingdevice and/or therapeutic element are within the ovary or outside theovary, or to sense where portions of the docking/guiding device and/ortherapeutic element are relative to the vasculature or other importantstructures. The sensing elements could also be used during treatment todynamically adjust treatment parameters. The sensing elements could beused to measure temperature and/or impedance. For example, atemperature-sensing element could be located on each of a plurality ofelectrodes. In some variations, two temperature-sensing elements couldbe located on a single electrode. Power could be adjusted based on thehottest temperature-sensing element or could be adjusted based on somecombination of the multiple sensing elements, such as an average orweighted average. In another example comprised of bipolar electrodes andtemperature sensing elements on each electrode, the active electrode(the electrode delivering the energy) could be interchanged with thereturn electrode before or during energy delivery based on the measuredtemperatures and/or impedances.

Furthermore, the sensing elements could also be used to detect if thedevice moves inappropriately during the treatment delivery. For example,device movement could be inferred by sensing sudden changes intemperature, impedance, and/or power. In one variation, the suddenchanges could be based on an instantaneous measurement exceeding somepredetermined threshold away from an averaged measurement. In anothervariation, the variance of a signal, such as power, could be trackedduring treatment and movement could be inferred when the variancedeviates by a predetermined threshold, such as a percentage difference.If movement is inferred, then the generator could automaticallyterminate energy delivery and/or inform the user that the device hasmoved.

When radiofrequency energy is employed, the generator may deliver theenergy at a power of 30 watts or less, and for a duration of 60 secondsor less. In some variations, the generator may deliver the energy at apower ranging from 4 to 15 watts, and for a duration of 10 to 45seconds. The radiofrequency energy may be supplied in a pulsed orcontinuous fashion. In other variations, the generator may deliver theenergy at a first power range (e.g., 0 to 30 watts or 4 to 15 watts) fora first duration (e.g., 10 to 45 seconds) followed by a second, higherpower range for a second, shorter duration (e.g., less than 10 seconds).The specific power settings may be pre-determined or may be determinedbased on current or previously acquired system feedback, such astemperature, impedance, power, and/or time. One example of usingpreviously acquired system feedback is to adjust the second, higherpower range based on the maximum power utilized during the firstduration. Applying higher power ranges or temperatures towards the endof the energy delivery can create different lesion characteristicsincluding, but not limited to, increased volume of tissue necrosis,cauterization of blood vessels, and enhanced echogenicity via increasedtissue desiccation, tissue contraction, and/or formation of steam ormicrobubbles. To prevent or minimize the amount of tissue deposition onthe therapeutic element due to the ablations (which could lead tosticking when retracting or deploying the therapeutic element), coatingsor surface treatments may be optionally applied to the any of thetherapeutic elements described herein. Examples of coatings includeParylene, PTFE, hydrogels, silicone oil, and oxidation. If the coatingis not electrically conductive, then additional surface treatments suchas acid etching or laser etching, could be selectively applied to thecoating to allow electrical energy to pass through.

FIG. 32 depicts an exemplary Power/Temperature Curve wherein energy isdelivered in a two-phased approach such that the first stage (S1) isdesigned to heat the tissue and a second stage (S2) is designed tochar/desiccate the tissue and/or cause steam and/or microbubbleformation. At the start of the energy delivery (t1) power is linearlyramped to a pre-set power (P1) over time, t2. Shortly after t2,temperature (A) is compared to a pre-determined target range (Tmin-Tmax)(e.g., 65 to 85 degrees C.). If temperature (A) is less than Tmin, powermay step or ramp up until the temperature is greater than Train. This isdepicted by power (P2) and temperature (B). As a safety feature, amaximum power may be set. As the tissue heats and changes itscharacteristics, temperature may also increase. Should the temperature(C) reach or exceed a pre-set maximum temperature (Tmax), either thetreatment could be terminated (not shown) or power could be reduced overtime (P3) until the temperature (D) once again falls below Tmax at time(t3). At the end of first stage (S1), the algorithm then enters thesecond stage (S2), where power ramps in a linear or step-wise fashion toa maximum power, Pmax and hold until time (t5), upon which energydelivery is terminated. The period defined by (t5-t4) may, for example,be between 3 to 10 seconds in order to char/dessicate/coagulate thetissue or cause steam and/or microbubble formation.

Alternatively, the generator may deliver power in a manner to achieve adesired target temperature but limit the power to some maximum power(e.g., 30 watts or less) in the event the target temperature cannot beachieved. FIG. 33 depicts an exemplary Power/Temperature Curve whereinenergy is delivered in a two-phased approach such that the first stage(S1) is designed to heat the tissue and a second stage (S2) is designedto char/dessicate the tissue or cause steam and/or microbubbleformation. At the start of the energy delivery (t1), power is linearlyramped until a minimum target temperature (Tmin) (e.g., 65 to 85 degreesC.) is reached. This event is denoted by power (P1) and temperature (A)at time (t2). As a safety feature, a maximum power may be set. Thegenerator then continually adjusts power in an effort to maintain theminimum temperature (Tmin) without exceeding a pre-set maximumtemperature (Tmax). As the tissue heats and changes characteristics, asudden increase in temperature may occur (not shown). Should thetemperature reach or exceed the maximum temperature (Tmax), thegenerator will adjust power down or terminate the treatment. At the endof the first stage (S1) which occurs at time (t3), the algorithm thenenters the second stage (S2), where power is ramped in a linear orstep-wise fashion to a second power, P2, and holds until time (t4), uponwhich energy delivery is terminated. The period defined by (t4-t3) may,for example, be between 3 to 10 seconds in order tochar/desiccate/coagulate the tissue or cause steam and/or microbubbleformation.

An exemplary system (5000) is illustrated in FIG. 23. In thisembodiment, the system is configured for monopolar energy delivery usinga neutral electrode (5002), which would be affixed to the skin of thepatient. Bipolar configurations would eliminate the need for anexternally-placed neutral electrode. For example, the therapeuticelement (5004) may be configured to have two or more electrodes ofapproximately the same size and spaced apart to deliver energy in abipolar or multi-polar fashion (not shown). Alternatively, the neutralelectrode (5002) may be incorporated into the docking/guiding device(5006). In a further variation, the neutral electrode may beincorporated into a cover placed over the transducer of the ultrasoundprobe or incorporated into the needle guide. In these cases, the neutralelectrode may be larger than the electrode located on the therapeuticelement such that only the electrode located on the therapeutic elementheats significantly. Furthermore, the sensing elements (5008) may beused to measure parameters either intra-procedurally orpost-procedurally to assess for technical success of the procedure. Forinstance, impedance changes could accompany desirable changes in tissuecharacteristics in successful treatment delivery.

Some variations of the system could be configured with bipolarelectrodes to deliver therapeutic doses of energy. Here a neutralelectrode (affixed to the skin of the patient, incorporated into thedocking/guiding device, or incorporated elsewhere away from the distalend of the device) could be utilized to measure impedance values fromone or each of the therapeutic electrodes before or during energydelivery. The impedance values between the therapeutic bipolarelectrodes and/or between a therapeutic electrode and the neutralelectrode could be used to determine the relative location of thetherapeutic elements within the ovary. An example is shown in FIGS. 34and 35A-35C. Therapeutic elements, such as electrodes, A and B could beconfigured in a bipolar manner such that energy is delivered from A andreturned to B (or vice versa) to generate a therapeutic effect.Impedance could also be measured between A and B. A neutral electrode,N, could be used to measure impedance from A to N and from B to N byapplying low, non-therapeutic levels of energy. Optionally oradditionally, a sensing element, C, could be located at the tip of thedevice to measure the impedance between C and N, A and C, and/or B andC. Comparing these different impedance measurements could providefeedback for the relative locations of A, B, and C.

FIGS. 35A-35C provide examples where electrode A and electrode B areboth inside the ovary. In FIG. 35B, electrode A is inside the ovary andelectrode B is partially outside the ovary. In FIG. 35A, the impedancesof A-to-N and B-to-N are similar since the electrical paths are similar.However, in FIG. 35B, the impedances of A-to-N and B-to-N could bemeasurably different depending on the composition of the non-ovariantissue-contacting electrode B. In one variation, the non-ovarian tissuecould be bowel filled with gas and result in higher impedance. Othertissues adjacent to the ovary that could result in higher impedance arefat deposits. In another variation, the non-ovarian tissue could bebowel, muscle, or a blood supply such that the impedance of B-to-N islower than the impedance of A-to-N. Based on these impedancemeasurements, the generator could provide the operator with differentfeedback regarding the relative location of the device. Similarly, FIG.35C depicts electrodes A and B within stromal tissue of the ovary andsensing element C within a follicle or cyst. Impedance measurementsA-to-B, A-to-C, and/or B-to-C (or optionally A-to-N, B-to-N, C-to-N),could be used to impute that the sensing element at the tip of thedevice is within a follicle and thus closer to the outer surface of theovary. Therefore, the generator could provide feedback to the operatorto stop advancing the device in order to prevent the tip fromunintentionally exiting the ovary. Additionally, if sensing element Cdid exit the ovary, the impedance measurements from A-to-B, A-to-C,and/or B-to-C (or optionally A-to-N, B-to-N, C-to-N) could be used todetect this condition.

According to embodiments described herein, which may partially or as awhole combine with other embodiments, it may be useful for the systemsto include features configured to maintain the orientation of the energydelivery elements, e.g., radiofrequency energy elements, in a singleplane, which may be desirable for visualization optimization. Thefeatures for maintaining planar orientation may include the use ofribbon and/or use of side ports on the guide/docking device to betterguide deployment. In other variations, orienting a planar therapeuticelement such that it is in plane with a 2-dimensional ultrasound fieldmay be accomplished by placing visual cues or identifiers (e.g., markerscomprised of an echogenic material; markers comprising echogenic bands,rings, arcs, or other geometric structures, etc.) or tactile cues oridentifiers (e.g., a wing-like structure) on a portion of the device,e.g., the proximal end of the device that deploys the therapeuticelement into the ovary. For transvaginal procedures, providing featuresfor maintaining the rotational orientation between the ultrasoundprobe/transducer, the guiding/docking device and/or the therapeuticelement may also be employed. FIG. 24 shows an exemplary system (6001)for maintaining therapeutic elements (6000) in the two-dimensional planewith the ultrasound visualization field/plane. For needle-guidedtransvaginal procedures, a needle guide (6002) is affixed to the shaftof the probe to ensure that the tip of the needle is always within thefield of view of the probe (6004). The needle guide (6002) may alsoensure that the needle enters the field of view from the same locationand travels along the same angle with respect to the head of theultrasound probe/transducer (6004). However, when therapeutic elementswith a curvilinear shape (6000) need to be deployed, planar orientationmust be maintained in order to see them as the probe (6004) or othersystem elements are manipulated. In one instance, the needle guide mayincorporate a unique geometry that mates with a guide on the dockingdevice. In this instance, an offset coupler (6006) may be affixed to theneedle guide (6002). The offset coupler (6006) may include a guide rod(6008), which can slide through an advancing handle (6010) by sliding anadvancing mechanism (6012) forward to force the therapeutic elements(6000) into the tissue. The advancing mechanism (6012) may then bepulled back to recapture the therapeutic elements (6000) when finished.

Referring to the embodiment shown in FIG. 26, a curvilinear therapeuticelement (7000) is shown within the ultrasound field of view (7002). Ifthe docking/guiding device (7004) and/or curvilinear element (7000) arerotated a few degrees with respect to the ultrasound transducer (7006),then the curvilinear element (7000) would no longer exist within thesame plane as the ultrasound visualization plane and the curvilinearelement would no longer appear on the ultrasound display. Therefore, theoperator would need to rotate the docking/guiding device (7004) and/orcurvilinear element (7000) until the curvilinear element reappeared onthe ultrasound display. This could increase procedure time and increasethe risk of patient injury by requiring additional manipulation of thedevice. It may also be beneficial to have an alignment feature thatorients or aligns the curvilinear element to the ultrasoundvisualization plane in a manner that ensures the curvilinear element isvisible as it deploys. Visualizing the entire element as it deploys mayallow the operator to more precisely position the element in the desiredlocation. In other embodiments, it may only be necessary to see thedistal tip of the curvilinear element (7000), to ensure that it is stillwithin the target tissue. Visualization of the distal tip of thecurvilinear element (7000), optionally combined with visualization ofthe distal tip of the docking/guiding device (7004), may provideadequate visualization for precise positioning.

In some cases, it may be desirable to have the ability to decouple andre-couple the docking/guiding device from the needle guide in situ. FIG.25 depicts an exemplary magnetic detachable needle guide (8000), whichmay be combined with other embodiments described herein. For example,the needle guide (8000) may incorporate a trough (8002) with embeddedneodymium magnets (8004) underneath it that may be used to position andhold a metallic docking/guiding device in place, while also making itremovable.

Alternative mechanisms for maintaining planar alignment are provided inFIGS. 27A to 27F. For example, an alignment adapter (9000) may beattached to a handle (9002) of a transvaginal ultrasound probe (9004).Alignment adapter (9000) may be removably attached to the ultrasoundprobe handle (9002) by snapping on, strapping, clampingcircumferentially via a two-piece or hinged clamshell, or other suitableways. In order to be adaptable to a variety of ultrasound probes, themating surface (9006, shown in the cross-sectional view of FIG. 27B) mayinclude features such as a low durometer or other suitably conformablepolymer (e.g., neoprene, polyurethane, silicone, etc). These featuresmay be molded into alignment adapter (9000) or provided as separateinsert pieces. The alignment adapter (9000) may further comprise areceiving lumen or cavity (9008) between the main body of the alignmentadapter and a guide (9010) of the guiding/docking device (9012). Thealignment adapter (9000) may also include an adjustable element (e.g., amechanical lock) (9014) that may be used to fix or hold steady theguiding/docking device (9012) or allow it to be moved. For example, whenthe adjustable element (9014) is in a locked (down) position (FIG. 27C),it aids in aligning the guiding/docking device (9012) and/or therapeuticelements (9016) within the ultrasound visualization plane. In theunlocked (up) position (FIG. 27D), the guiding/docking device (9012) maybe freely rotated (or rotation may be limited to, for example, about 90degrees in a clockwise or counter-clockwise direction). Additionally,the alignment adapter could allow some limited rotation, such as plus orminus up to 20 degrees of rotation, even in the locked position. Forexample, the opening in the mechanical lock (9014) could be enlargedsuch that the guide (9010) could rotate about 10 degrees in the lockedposition, The limited rotation can be useful in maintaining thetherapeutic elements within the ultrasound visualization plane whileallowing the operator to quickly rotate the device back and forth toenhance visualization due to the motion. Similarly, subtle motion (forthe purpose of enhanced visibility) could be achieved by allowing theoperator to easily shift the therapeutic elements a small distancedistally and proximally, such as plus or minus up to 0.25 mm. Theadjustable element may comprise a notch configured to mate with thedocking device to help effect locking. The docking/guiding device (9012)may be introduced while the adjustable element (9014) is in the unlockedposition (FIG. 271)) or in a partially-locked position (FIG. 27E) wherethe guide (9010) need not be perfectly straight and will aid in aligningthe docking/guiding device (9012) as it is lowered. The geometry of theadjustable element (9014) may also be tapered such that thedocking/guiding device (9012) may rest in proper alignment but still befree to rotate easily, if desired. If rotation or translation of thedocking/guiding device (9012) is desired, it may further incorporate ahub (9020) to make manipulation easier. Furthermore, the alignmentadapter (9014) may further comprise sliders, knobs, and/or levers, whichcan be used to advance/withdraw the docking/guiding device,deploy/retract therapeutic elements, engage/disengage the alignmentmechanism, etc. Due to the alignment feature, the therapeutic elementscan be maintained within the visualization plane of the ultrasound probeduring an ovarian procedure.

For example, as illustrated in FIG. 27F, mechanical lock (not shown) maybe used to orient a curvilinear element in a first planar orientation(9022) followed by retraction and redeployment in a second planarorientation (9024), allowing for two treatments to be applied within thesame visualization plane (9026) of the ultrasound probe.

In the embodiment shown in FIG. 28, the alignment adapter (9028) can bea lock that is removably affixed to the handle of the ultrasound probe(9030) via a. temporary adhesive located at the interface between thealignment adapter (9020) and ultrasound probe (9030). The adapter couldalso be attached with a conformable strap or clamp. Here alignmentadapter (9028) includes a receiving alignment channel (9032) with ageometry that prevents or limits rotation once engaged (e.g., square orrectangular). The proximal end of a guiding/docking device (9036)incorporates an alignment element (9034), which mates with the receivingalignment channel (9032) to maintain the planar orientation of thetherapeutic elements (9042) and the visualization plane of theultrasound probe. As described previously, the alignment mechanism couldallow some limited rotational or translational motion to enhancevisualization. For example, the alignment channel (9032) could be largerthan the alignment element (9034) by 0.025 cm which would allow somerotation but still maintain the therapeutic element within theultrasound visualization plane. The guiding/docking device (9036)further comprises a handle (9040), which may be used to manipulate thedevice and/or may further incorporate features for deploying thetherapeutic elements (9042). Such deploying features may include aslider, knob, wheel, crank, and/or levers, which can be used todeploy/retract therapeutic elements (9042).

According to embodiments described herein, which may partially or as awhole combine with other embodiments, the guiding/docking device maycomprise a handle, which may be used to manipulate the device and/or mayfurther incorporate features for deploying the therapeutic elements aswell as incorporating features to limit the travel of theguiding/docking device. Since the distal tip of the guiding/dockingdevice may contain a needle (or otherwise sharp) point to pierce throughthe vaginal wall and capsule of the ovary, it may be desirable toprevent the needle tip from traveling too far distally and causingunintentional injury. In one embodiment, as shown in FIG. 36A, thehandle (not shown) could provide tactile and/or visual feedback toinform the operator that the needle tip (411) of the guiding/dockingdevice (409) is located at the distal end of the needle guide (401).This point can be referred as the zero point. Maintaining the needle tipat the zero point can prevent the needle tip from contacting the vaginalwall (403) while the operator manipulates the ultrasound probe (405) forvisualization and/or device placement. Furthermore, the handle couldcontain a limiting mechanism that limits the distal travel of theguiding/docking device to prevent the needle tip from exiting mostovaries during the initial needle puncture, e.g., a travel distance ofabout 3 cm (or e.g., about 1.5 to about 4 cm) from the zero point wherethe guiding/docking device can freely travel back and forth as long asthe tip does not exceed the maximum travel distance. Once the operatorinserts the docking/guiding device (409) into the ovary (407) (as shownin FIG. 36B), then the operator may release the limiting mechanism onthe handle. Additionally or optionally, the handle may comprise amechanism to allow the operator to adjust the maximum travel distance.This would allow the operator to insert the needle tip (411) moredistally towards the capsule of the ovary (407) (as shown in FIG. 36C)and define a new maximum travel distance for the needle tip (411). Thiscould prevent the operator from inadvertently advancing the needle tipbeyond the ovary and could also prevent the needle tip from exiting theovary in the event the ovary were to move due to patient respiration orother patient movement.

In other variations, the travel of the guiding/docking device may hecontrolled by increasing friction as it is advanced but can be retractedwith less friction. Another variation could include a limiting mechanismsuch that the guiding/docking device and handle can only be advancedabout 3 cm (or e.g., about 1.5 to about 4 cm) from the zero point. Thenanother mechanism in the handle, such as a wheel, lever, or slider,could be used to advance the guiding/docking device further into theovary. This would prevent gross motions of the handle from advancing theneedle tip beyond the ovary.

As previously stated, non-invasive treatment systems may he employed.FIG. 37 depicts an exemplary non-invasive treatment system. Referring tothe figure, system (501) is comprised of an imaging and/or therapeuticelement (503), configured for contact with the abdomen (505) of apatient (507); a connection (509) (e.g., cable) for connecting theimaging and/or therapeutic element (503); and a console (511),comprising a user interface (513), a feedback control system (515), oneor more ultrasound sources (517) configured for imaging or applicationof energy to affect target tissue, and a mechanism for interpretingimaging data to enable targeting of desired target tissue.

Target tissues of an ovarian procedure may include the following:follicles, follicles of a particular size range (e.g., pre-antralfollicles), stroma, thecal cells, stromal cells, granulosal cells,mesovarium., or nerves. In one instance, follicles, stroma, or thecalcells could be preferentially targeted and the vasculature could berelatively avoided. In another instance, the settings of the therapeuticelement could be selected such that nerves are targeted and thevasculature could be relatively spared. in another instance, the cortexof the ovary could be targeted, and the stroma of the ovary could berelatively spared. In another instance, the stroma of the ovary could betargeted, and the ovarian cortex could be relatively spared. In anotherinstance, the interface of the stroma and cortex could be preferentiallytargeted. In another instance, the mesovarium could be preferentiallytargeted. In another instance, the granulosal cells in antral andpre-antral cells may be preferentially targeted. In a further instance,the nerves in the pedicle of tissue connecting the ovary to surroundingtissues (i.e., mesovarium) could be targeted using treatment methodsthat spare the nearby vasculature (e.g., cryotherapy, selectiveheating/ablation, electroporation). Certain tissues (e.g., nerves) maybe more susceptible to destruction at lower ablation thresholds, suchthat those tissues could be preferentially targeted. Some tissues mayhave particular acoustic or material properties (e.g., fluid-filledfollicles) such that some forms of energy (e.g., ultrasound) could beused to specifically target those tissues. For example, in the case ofHIM, ultrasound imaging could be used to map the location of thefollicles in the cortex of the ovary, and then. energy could be directedto regions proximate to follicles clearly visible on ultrasound.

After or while delivering the therapeutic element, aspiration could beperformed either through the guiding/docking device, through thetherapeutic element, or through a device that contains both a dockingand therapeutic element. The aspiration could be used to assist inreduction of cyst size, to assess if bleeding is controlled, to collectfluid for analysis, to remove any space created between tissues usingfluid or gas, or for another purpose. The aspiration port could also beused to inject gas or other material, which might be used to changeimaging characteristics of that region of the ovary; this could be usedto label/mark portions of the ovary that had already been treated.

At the conclusion of the procedure, the docking element, the therapeuticelement, or a combination thereof could be used to deliver materials,active agents, etc. to assist in the healing process and prevent theformation of adhesions. Some examples of these are the commerciallyavailable agents Interceed® Absorbable Adhesion Barrier (Ethicon,Somerville, N.J.), Seprafilm® Adhesion Barrier (Genzyme, Bridgewater,N.J.), and Adept® Adhesion Reduction Solution (Baxter, Deerfield, Ill.).These and other agents made of modified sugars, cellulose, fabrics, andcolloids have been used in other surgical cases to minimize thefrequency of surgical adhesions.

It is contemplated that in certain cases where the desired clinicaleffect was not achieved or where it was achieved but then subsequentlythe condition re-occurred, repeat procedures could be needed. In thesecases, it might be necessary to target a different portion of the ovary,different cysts, or a different portion of the mesovarium. The inventorscontemplate the need for using the system to specifically re-treat thesame portion of tissue as the original treatment or a distinctlydifferent potion of tissue from the first intervention.

III. EXEMPLARY COMBINATIONS OF FEATURES

The following tables disclose various features of the methods andsystems provided herein that can be combined to manipulate ovariantissues and/or treat PCOS.

In Table 1, exemplary combinations of features for transvaginal,laparoscopic, percutaneous, or via a natural orifice route through thevagina-uterus-fallopian tubes approaches are provided.

TABLE 1 Column 7 Column 3 Column 4 Pattern of Column 8 Column 1 Column 2Tissue Ovary Column 5 Column 6 Therapeutic Aspiration/ AccessVisualization Separation docking Landmarks Therapeutic MechanismDelivery Compression Transvaginal transvaginal fluid suction/ ovarianTissue Heat Ablation [FRY (monopolar, Superior aspiration ultrasoundaspiration/ features bipolar, multimodal), HIFU, Direct Heat, at ovaryvacuum cysts microwave, unfocused/partially focused interfaceultrasound, laser, saline/water, steam] Laparoscopic transabdominal airconcave bony Tissue Warning [RF (monopolar, bipolar, Near aspirationultrasound surface multimodal), HIFU, Direct Heat, vasculature/ withinmicrowave, unfocused/partially focused mesovarium ovary ultrasound,laser, saline/water, steam] Via a natural CT mechanical hook/needlebroad non-thermal acoustic cavitation away from aspiration orifice routescaffold ligament/ vasculature/ to area through the ovary mesovariumsurrounding vagina-uterus junction ovary fallopian tubes Percutaneous MRmechanical abrasive Cryoablation (cooled element, liquid Maximize ovaryballoon surface nitrogen, CO2, dry-ice) interruption external of cystscompression endoscopic none lasso Tissue Cooling (cooled element,preferential ovary visualization saline/water) for cortical internalovary compression OCT Mechanical disruption preferential none formedullary ovary virtual drug - Implant permanent or delivery histologybiodegradeable vs. no-implant, types of to limit/ drugs: beta-blockers,anti-androgens, minimize neurotoxins, or tissue toxins, 5-alpha-disruption reductase inhibitors, or aromatase of ovarian inhibitorscapsule ultrasound mechanical implant (permanent vs. delivery on guideor biodegradeable), could be activated to maximize therapeuticexternally disruption element of ovarian capsule Notes: specificembodiment may include none of features in a column or more than onefeature in a column; oocyte harvesting may be done pre-procedure; eitherthe guiding element or the treatment element or the combinedguiding/treatment element may be steerable; optional anti-adhesivematerials may be delivered to prevent adhesion formation, therapeuticelement could be irrigated

In Table 1 (transvaginal, laparoscopic, percutaneous, or via a naturalorifice route through the vagina-uterus-fallopian tubes approaches),visualization of the procedure and/or tissues could be performed usingany of the visualization techniques described in the 2nd column, tissueseparation may be done via any of the techniques described in the 3rdcolumn, the ovary could be engaged and the device could dock on theovary via any of the techniques in the 4th column, any of the tissuelandmarks that could be used in aiding the procedure are listed in the5th column, any of the therapeutic mechanisms that may employed by thedevice are described in the 6th column, possible patterns of therapydelivery are listed in column 7, and the various options for aspirationor ovarian compression that may be used in any of the embodiments arelisted in column 8.

Table 2 provides exemplary combinations of features that could be usedfor open surgical approaches.

TABLE 2 Column 6 Column 3 Pattern of Column 7 Column 1 Column 2 OvaryColumn 4 Column 5 Therapeutic Aspiration/ Access Visualization dockingLandmarks Therapeutic Mechanism Delivery Compression surgicaltransvaginal suction/ ovarian features Tissue Heat Ablation [RF(monopolar, Superior aspiration at ultrasound aspiration/ cysts bipolar,multimodal), HIFU, Direct Heat, ovary interfere vacuum microwave,unfocused/partially focused ultrasound, laser, saline/water, steam] CTconcave bony Tissue Warming [RF (monopolar, bipolar, Near vasculature/aspiration within surface multimodal), HIFU, Direct Heat, mesovariumovary microwave, unfocused/partially focused ultrasound, laser,saline/water, steam] MR hook/needle broad ligament/ non-thermal acousticcavitation away from aspiration to ovary junction vasculature/ areamesovarium surrounding ovary direct abrasive Cryoablation (cooledelement, liquid Maximize ovary external visualization surface nitrogen,CO2, dry-ice) interruption of cysts compression endoscopic lasso TissueCooling (cooled element, preferential for ovary internal visualizationsaline/water) cortical ovary compression OCT Mechanical disruptionpreferential for none medullary ovary virtual drug - implant permanentor delivery to histology biodegradeable vs. no-implant, types oflimit/minimize drugs: beta-blockers, anti-androgens, disruption ofovarian neurotoxins or tissue toxins, 5-alpha- capsule reductaseinhibitors, or aromatase inhibitors ultrasound mechanical implant(permanent vs. delivery to maximize on guide or biodegradeable), couldbe activated disruption of ovarian therapeutic externally capsuleelement Notes: specific embodiment may include none of features in acolumn or more than one feature in a column, oocyte harvesting may bedone pre-procedure; either the guiding element or the treatment elementor the combined guiding/treatment element may be steerable; optionalanti-adhesive materials may be delivered to prevent adhesion formation,therapeutic element could be irrigated

In Table 2 (surgical approaches), visualization of the procedure and/ortissues could be performed using any of the visualization techniquesdescribed in the 2nd column, the ovary could be engaged and the devicecould dock on the ovary via any of the techniques in the 3rd column, anyof the tissue landmarks that could be used in aiding the procedure arelisted in the 4th column, any of the therapeutic mechanisms that mayemployed by the device are described in the 5th column, possiblepatterns of therapy delivery are listed in column 6, and the variousoptions for aspiration or ovarian compression which may be used in anyof the embodiments are listed in column 7.

Other methods may include the non-invasive targeted delivery of energyto ovarian tissues. Table 3 provides exemplary combinations of elementsthat could be used to construct a system/device for such delivery ofenergy.

TABLE 3 Column 5 Pattern of Column 6 Column 1 Column 2 Column 3 Column 4Therapeutic Aspiration/ Access Visualization Landmarks TherapeuticElement Delivery Compression non-invasive transvaginal ovarian featuresTissue Heat Ablation [RF (monopolar, Superior (external) ultrasoundcysts bipolar, multimodal), HIFU, Direct Heat, microwave,unfocused/partially focused ultrasound, laser, saline/water, steam]transabdominal bony Tissue Warming [RF (monopolar, bipolar, Nearvasculature/ ultrasound multimodal), HIFU, Direct Heat, mesovariummicrowave, unfocused/partially focused ultrasound, laser, saline/water,steam] CT non-thermal acoustic cavitation MR broad ligament/Cryoablation (cooled element, liquid away from ovary external ovaryjunction nitrogen, CO2, dry-ice) vasculature/ compression mesovariumfiducial Tissue Cooling (cooled element, Maximize saline/water)interruption of cysts Mechanical disruption preferrential for medullaryovary drug - implant permanent or preferential for biodegradeable vs.no-implant, types of medullary ovary drugs: beta-blockers,anti-androgens, neurotoxins or tissue toxins, 5-alpha-reductaseinhibitors, or aromatose inhibitors mechanical implant (permanent vs.delivery to biodegradeable), could be activated limit/minimizeexternally disruption of ovarian capsule delivery to maximize disruptionof ovarian capsule Notes: specific embodiment may include none offeatures in a column or more than one feature in a column

In one variation, non-invasive imaging may also be employed topercutaneously or via a natural orifice route through thevagina-uterus-fallopian tubes place at least one fiducial within thepatient, e.g., in the proximity of the target ovarian tissue, which maybe used during the delivery of therapy to target treatment locations.Fiducials may be constructed of any material chosen for biocompatibilityand compatibility with the desired imaging modality used during thetherapeutic procedure. The fiducial may be placed either percutaneouslyor via a natural orifice route through the vagina-uterus-fallopian tubesvia a needle, microcatheter, or other suitable delivery system throughthe abdominal wall, transvaginally, laparoscopically, or surgically.

In another variation, a device could be placed within the vagina. Thedevice may be used with integrated imaging or use of a non-integratedimaging device (e.g., transvaginal ultrasound or abdominal ultrasound)to deliver either mechanical manipulation (e.g., sound, vibration, orother mechanical manipulation) or energy (e.g., electrical current)preferentially to the ovaries or portions of the ovaries. In the case ofenergy delivery, this could be either an ablative or non-ablative (e.g.,energy similar to that used in transcutaneous electrical nervestimulation) form of energy. This could be done repeatedly in a singlesession or temporally spaced as necessary.

IV. EXAMPLES

The following examples further illustrate embodiments of the systems andmethods disclosed herein, and should not be construed in any way aslimiting their scope.

Example 1: Ablation Volume with a Bipolar System Including a StraightTherapeutic Element and Using Max Power of 4 Watts

An ovarian tissue apparatus having a bipolar electrode configuration wascreated using two Platinum-Iridium (90%110%) bands mounted on a straightpolymer shaft. The electrode outer diameters were 1.27 mm and thelengths were 3.0 mm. The electrodes were spaced 3.0 mm apart from eachother and a temperature sensor was mounted on the inner diameter of eachelectrode. To evaluate lesion (ablated tissue) sizes, raw chicken breastwas placed around the electrodes and a RF generator delivered energy toone electrode while the other electrode was used as part of the returnpath to the generator. RE energy was delivered for 30 seconds in orderto achieve a target temperature of approximately 80° C. The maximumpower observed was approximately 4 watts. A cross-section of theresulting lesion (cut lengthwise) showed apparent tissue necrosismeasuring 3.8 mm wide and 10.4 mm long, Approximating the lesion volumeas a cylinder (with diameter of 3.8 mm and length of 10.4 mm andvolume=¼×π×D2×L), the lesion was calculated to have a volume of ablatedtissue of 118 mm³. While this experiment was conducted with a straighttherapeutic element, similar results would be expected using a curvedtherapeutic element.

Example 2: Ablation Volume with a Bipolar System Including a StraightTherapeutic Element and Using Max Power of 10 Watts

A similar experiment was conducted with the same electrode configurationdescribed in Example 1. In this example, however, RE energy wasdelivered for a total of 15 seconds and targeted a maximum temperatureof approximately 100° C. The maximum power utilized in this case wasapproximately 10 watts. A cross-section of the resulting lesion showedapparent tissue necrosis approximating an ellipse with a major axis, D1,of 4.5 mm and minor axis, D2, of 3.9 mm. Assuming a lesion length of 10mm, the resulting lesion volume was calculated as 138 mm³ (wherevolume=¼×π×D1×D2×L).

Example 3: Ablation Volume with a Bipolar System Including a CurvedTherapeutic Element

Experiments were conducted utilizing a similar bipolar electrodeconfiguration as described in Example 1. However, the electrodes weremounted on a curved polymer shaft with an approximate radius of 7 mm.Both Platinum-Iridium (90%/10%) electrodes had outer diameters of 1.27mm and lengths of 3.0 mm. The electrodes were spaced 3.0 mm apart fromeach other and a temperature sensor was mounted on the inner diameter ofeach electrode. In one experiment, RF energy was delivered for 30seconds in order to achieve a target temperature of approximately 90° C.A cross-section of the resulting lesion (cut lengthwise) showed apparenttissue necrosis measuring 6.7 mm wide. In another experiment, RF energywas also delivered for 30 seconds in order to achieve a targettemperature of approximately 90° C. A cross-section of the resultinglesion showed apparent tissue necrosis approximating an ellipse with amajor axis, D1, of 6.0 mm and minor axis, D2, of 3.8 mm. Assuming alesion length of 9 mm, the resulting lesion volume can he estimated as161 mm³ (where volume=¼×π×D1×D2×L).

V. FURTHER EXAMPLES

Furthermore, the following examples, including any of the indicatedcon⁻ibinations thereof, are disclosed herein and are comprised withinthe scope of the present disclosure.

1. A systemfor performing an ovarian procedure comprising:

a) an ovarian tissue apparatus, the ovarian tissue apparatus comprisinga docking device and a therapeutic element, the docking devicecomprising an elongate body and having a proximal end, a distal end, anddefining a lumen therethrough, and the therapeutic element beingslidable within and deployable from the lumen of the docking device;

b) a transvaginal probe comprising a handle and an ultrasoundtransducer;

c) a mechanical lock or a visual identifier on a part of the system; and

d) a generator configured to supply energy to the therapeutic element,

wherein the mechanical lock or visual identifier is configured tomaintain planar orientation of the therapeutic element relative to theultrasound transducer and during a procedure on an ovary.

2. The system of example 1, wherein the therapeutic element comprisesone or more curved structures, the curved structures comprisingelectrodes and having a straightened length and radius of curvature.

3. The system of example 1 or example 2, wherein the therapeutic elementcomprises two curved structures.

4. The system of example 2 or example 3, wherein the straightened lengthranges between about 5.0 and about 40 mm.

5. The system of any of examples 2-4, wherein the radius of curvatureranges between about 3.0 and about 10 mm.

6. The system of example 1, wherein the therapeutic element comprises acurved electrode.

7. The system of any of the preceding examples, wherein the therapeuticelement comprises an elongate body having a straightened length and aradius of curvature, an active electrode, and a return electrode.

8. The system of example 7, wherein the straightened length rangesbetween about 5.0 and about 40 mm.

9. The system of example 7 or example 8, wherein the radius of curvatureranges between about 3.0 and about 10 mm.

10. The system of any of examples 1-9, wherein the mechanical lockcomprises an adjustable element having a locked position and an unlockedposition.

11. The system of example 10, wherein the adjustable element comprises anotch configured to mate with the docking device when the alignmentadapter is in the locked position.

12. The system of any of examples 1-11, wherein the generator isconfigured to supply radiofrequency energy at a power of 30 watts orless, and for a duration of 20 seconds or less.

13. The system of any of examples 1-12, wherein the generator isconfigured to supply^(,) continuous or pulsed radiofrequency energy.

14. The system of any of examples 1-13, wherein the distal end of thedocking device comprises one or more attachment elements for releasablysecuring an ovary.

15. The system of example 14, wherein the one or more attachmenttscomprise a hook, needle, or barb.

16. The system of any of examples 1-15, wherein the therapeutic elementcomprises an echogenic material.

17. The system of any of examples 1-15, wherein a portion of thetherapeutic element comprises an echogenic material,

18. The system of any of examples 1-17, wherein a portion of the dockingdevice comprises an echogenic material.

19. The system of any of example 1, wherein the therapeutic elementcomprises an electrode, a cryoablation element, a cooling element, alaser, or a combination thereof.

20. A method for treating polycystic ovary syndrome comprising:

a) advancing a probe comprising a handle, an ultrasound transducer, anda needle guide into the vaginal canal;

b) advancing an ovarian tissue apparatus into the needle guide, theovarian tissue apparatus comprising a docking device and a therapeuticelement;

c) advancing the docking device through a vaginal wall;

d) penetrating an ovary at a single entry point with the docking deviceor the therapeutic element;

e) advancing the therapeutic element from the docking device into theovary;

f) delivering energy to affect a volume of tissue within the ovary usingthe therapeutic element to treat a symptom of polycystic ovary syndrome:

g) retracting the therapeutic element into the docking device: and

h) removing the ovarian tissue apparatus.

21. The method of example 20, further comprising repositioning thetherapeutic element and repeating the step of energy delivery throughthe single entry point.

22. The method of example 20 or example 21, wherein the step of energydelivery comprises ablating a volume of tissue.

23, The method of any of examples 20-22, wherein advancement of thetherapeutic element occurs in the same plane as the imaging plane.

24. The method of any of examples 20-23, wherein the affected volume oftissue ranges from about 240 mm³ to about 3000 mm³.

25. The method of any of examples 20-24, wherein the affected volume oftissue ranges from about 30 mm³ to about 3000 mm³.

26. The method of any of examples 20-23, wherein the affected volume oftissue ranges from about 3 to 20% of the ovary.

26. The method of any of examples 20-26, wherein the delivered energy isradiofrequency energy.

27. The method of example 26, wherein the radiofrequency energy isdelivered for 15 to 45 seconds.

28. The method of example 26 or example 27, wherein the power of theradiofrequency energy is 30 watts or less.

29. The method of any of examples 26-28, wherein delivery of theradiofrequency energy is continuous or pulsed.

30. The method of any of examples 20-29, wherein the therapeutic elementcomprises one or more curved structures, the curved structurescomprising electrodes and having a straightened length and radius ofcurvature.

31. The method of example 30, wherein the therapeutic en comprises twocurved structures.

32. The method of example 30 or example 31, wherein the straightenedlength ranges between about 5.0 and about 40 mm.

33. The method of any of examples 30-32, wherein the radius of curvatureranges between about 3.0 and about 10 mm.

34. The method of example 20, wherein the therapeutic element comprisesa curved electrode,

35. The method of example 20, wherein the therapeutic element comprisesan elongate body having a straightened length and a radius of curvature,an active electrode, and a return electrode.

36. The method of example 35, wherein the straightened length rangesbetween about 5.0 and about 40 mm.

37. The method of example 35 or example 36, wherein the radius ofcurvature ranges between about 3.0 and about 10 mm.

38. The method of any of examples 20-37, wherein the symptom ofpolycystic ovary syndrome is infertility.

1. A method for treating polycystic ovary syndrome comprising: advancinga docking device into a needle guide of an ultrasound probe, theultrasound probe further comprising a probe handle and an ultrasoundtransducer, the docking device comprising a therapeutic element slidablewithin and deployable from a lumen of the docking device; advancing theultrasound probe and the docking device into the vaginal canal; imagingthe ovary using the ultrasound transducer in an imaging plane; advancingthe docking device through a vaginal wall; penetrating an ovary at asingle entry point with the docking device or the therapeutic element;advancing the therapeutic element from the docking device into the ovaryin the same planar orientation as the imaging plane; and deliveringenergy to affect a volume of tissue within the ovary using thetherapeutic element to treat a symptom of polycystic ovary syndrome. 2.The method of claim
 1. wherein about 3% to about 20% of the tissuewithin the ovary is affected by the delivered energy.
 3. The method ofclaim 1, wherein the step of delivering energy is repeated through thesingle entry point in the ovary.
 4. The method of claim 1, wherein thedelivered energy is radiofrequency energy.
 5. The method of claim 4,wherein the radiofrequency energy is delivered for about 20 seconds toabout 60 seconds.
 6. The method of claim 5, wherein the therapeuticelement comprises an elongate body having a straightened length and aradius of curvature, an active electrode, and a return electrode.
 7. Themethod of claim 6, wherein the straightened length ranges between about5.0 and about 40 mm.
 8. The method of claim 7, wherein the radius ofcurvature ranges between about 3.0 mm and about 10 mm.
 9. The method ofclaim 1, further comprising maintaining the planar orientation of thetherapeutic element relative to the ultrasound transducer during one ormultiple ablation procedures on the ovary.
 10. The method of claim 1,further comprising coupling an alignment element coupled to the dockingdevice to the ultrasound probe via an adapter removably coupled to theprobe handle, the adapter comprising a receiving alignment channelhaving a geometry that allows engagement with the alignment element in amanner that maintains planar orientation and limits rotation of thedocking device and therapeutic element relative to the ultrasound probeduring one or multiple ablation procedures on the ovary.
 11. A methodfor treating polycystic ovary syndrome comprising: advancing a dockingdevice into a vaginal canal of a patient; penetrating a vaginal wall andovary of the patient via a distal tip of the docking device; advancing atherapeutic element from the docking device into the ovary; anddelivering energy to affect a volume of tissue within the ovary via thetherapeutic element to treat a symptom of polycystic ovary syndrome. 12.The method of claim 11, wherein penetrating the vaginal wall and ovaryof the patient comprises penetrating the vaginal wall and ovary of thepatient at a single entry point.
 13. The method of claim 11, wherein thedelivered energy is radiofrequency energy.
 14. The method of claim 11,wherein the volume of tissue within the ovary comprises a polycysticovary or ovarian cyst.
 15. The method of claim 11, wherein deliveringenergy to affect the volume of tissue within he ovary comprisesdelivering energy for 20 to 60 seconds.
 16. The method of claim 11,further comprising imaging the ovary via an ultrasound transducer in afield of view of the ultrasound transducer.
 17. The method of claim 16,wherein advancing the therapeutic element from the docking device intothe ovary comprises advancing the therapeutic element from the dockingdevice into the ovary in the field of view of the ultrasound transducer.18. The method of claim 16, further comprising maintaining anorientation of the therapeutic element relative to the ultrasoundtransducer during one or more additional deliveries of energy within theovary.
 19. The method of claim 11, further comprising reorienting thedocking device within the field of view of the ultrasound transducerwithin the ovary, and then delivering additional energy within the ovaryvia the therapeutic element for one or more additional deliveries ofenergy within the ovary.
 20. The method of claim 11, further comprisingremovably coupling the docking device to a handle of a transvaginalprobe via an adapter removably coupled to the handle of the transvaginalprobe.